探討JAK/STAT /SOCS 之訊息傳導路徑於口腔癌細胞的調控機轉

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彭軒鈺(Hsuan-Yu Peng) 查詢紙本館藏

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論文名稱

探討JAK/STAT /SOCS 之訊息傳導路徑於口腔癌細胞的調控機轉
(Regulatory Mechanisms of JAK/STAT/SOCS Signaling Pathways in Oral Cancer Cells)

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摘要(中)

細胞因子信號轉導抑制因子（Suppressor of cytokine signaling, SOCS）蛋白家族有八名成員，即SOCS1~7及CIS。SOCS 蛋白家族主要結構有：N 端可變區、SH2 結構域和SOCS 區域 (SOCS box)。其中SH2 結構域和SOCS 區域是SOCS 調節信號轉導途徑所必需的功能區域，具有負回饋抑制JAK/STAT (janus kinase/signal transducer and activator of transcription) 訊息傳導的功能。近年來，發現SOCS家族成員在癌症中發揮重要作用，但仍然有許多功能和機制還需要進一步探討及研究。在本論文第一部分的研究裡我們發現到40對口腔癌患者的SOCS2蛋白表現量較低，與目前研究發現在許多實體器官惡性腫瘤中SOCS2 的表現受到抑制不謀而合。加上這幾年microRNA(簡稱miRNA)在癌症的角色愈發重要，所以我們想要探討miRNA在口腔癌是否扮演抑制SOCS2的角色。我們利用miRNA資料庫來預測可能標靶SOCS2的miRNA，發現miR-424-5p在病人miRNA array與兩個miRNA資料庫是唯一重疊的miRNA。我們之後證明當在口腔癌細胞抑制miR-424-5p表現可以增加SOCS2蛋白的表達及抑制STAT5活化。我們也發現白細胞介素-8 （Interleukin-8，IL-8）會增加miR-424-5p的表現，進一步抑制SOCS2表達而活化STAT5訊號路徑，最後導致口腔癌細胞的遷移、入侵。有趣的是，我們發現IL-8是透過活化STAT5而誘導miR-424-5p表現上升，導致口腔癌細胞的侵襲和轉移。這部分的研究結果，我們確定了一種新的機制， mir-424-5p導致的口腔癌進展，是建立在IL-8、mir-424-5p、SOCS2和STAT5信號通路之間的功能性連接。在第二部分的研究，我們主要探討新穎微管抑制劑MPT0B098 對口腔癌細胞的影響。MPT0B098是根據亞培藥廠第二期人體臨床試驗之ABT-751結構、設計並合成全新骨架的磺胺類小分子化合物。在我們實驗結果發現 MPT0B098會抑制口腔癌細胞株的生長，並誘導口腔癌細胞發生細胞凋亡。同時，我們也發現MPT0B098抑制JAK/STAT3訊息傳導的功能是透過誘導口腔癌細胞中SOCS3蛋白量。由於目前沒有人探討微小管和SOCS3之間的關係，在我們的研究發現微小管和SOCS3有密切的關係，或許 SOCS3可以是用於MPT0B098治療潛在的治療靶。我們也發現MPT0B098結合順鉑或5-FU所抑制口腔癌細胞的效果，比順鉑結合5-FU為比更好。
在這些研究中，我們希望這個微管蛋白抑製劑，MPT0B098，可以做為治療口腔癌的潛力發展藥物。從以上實驗中我們得知SOCS2 和SOCS3 在口腔癌發生的過程中，扮演重要的抑癌基因角色，也在上述的實驗發現 JAK/STAT 訊息路徑中的負回饋調節者 (例如SOCS2 和SOCS3)，不僅可受到藥物誘導也可被其他機轉調控，這對於未來口腔癌治療藥物的開發及應用有很大的幫助及發展。

摘要(英)

The family of suppressors of cytokine signaling (SOCS) consists of eight members, including SOCS1–7 and CIS. The main structure of SOCS includes a variant region at the N-terminus, SH2 domain, and SOCS box. The SH2 domain and SOCS box are the essential regions for regulating the signaling pathway, with the negative feedback inhibition of janus kinase/signal transducer and activator of transcription (JAK/STAT). In recent years, SOCS family members have been found to play important roles in cancer. However, many functions and mechanisms still need further identification and validation. In the first part of the study, we found that the SOCS2 expression level was lower in 40 patients with oral cancer, and this is consistent with the current findings that SOCS2 expression is inhibited in many malignant solid tumors. Recently, the role of microRNA (miRNA) in cancers development has attracted more attention. Thus, we attempted to investigate the role of miRNA in inhibiting SOCS2 in oral cancer. Using targeting algorithms (miRNAmap and microRNA.org) combined with OSCC patients′ miRNA microarray data, we wanted to search for putative miRNAs that might bind to SOCS2 mRNA. Based on the computational screening, we identified one miRNA, miR-424-5p, which was significantly upregulated in OSCC tumors compared with their corresponding normal samples (p < 0.0001). We later proved that the inhibition of miR-424-5p expression in oral cancer cells increased SOCS2 expression and inhibits STAT5 activity. It was also shown that interleukin-8 (IL-8) increases miR-424-5p expression, further inhibited SOCS2 expression, and activated STAT5 signaling pathway. Interestingly, IL-8 induces miR-424-5p expression, resulting in the proliferation and invasion of oral cancer cells via activating STAT5. From these results, a new mechanism was established, i.e., miR-424-5p mediates the progression of oral cancer by functionally connecting the signaling pathway among IL-8, miR-424-5p, SOCS2, and STAT5. In the second part of the study, the effect of a novel microtubule inhibitor, MPT0B098, on oral cancer cells was investigated. MPT0B098 is a newly synthesized sulfonamide-type small-molecule compound that was designed based on the structure of ABT-751, which was at Phase II clinical trial from Abbott. The results showed that MPT0B098 inhibited the growth of oral cancer cell lines and induced apoptosis in oral cancer cells. It was found that MPT0B098 inhibited JAK/STAT3 signaling via increasing the protein level of SOCS3 in oral cancer cells. The relationship between microtubule and SOCS3 is currently unknown, and our study showed that microtubule is closely related to SOCS3. Therefore, SOCS3 could be a potential treatment target for MPT0B098 treatment. The effect of inhibiting cancer cell lines by combining MPT0B098 with either cisplatin or 5-fluorouracil (FU) was found to be better than that by combining cisplatin and 5-FU. In these studies, we hope to show that this microtubule inhibitor, MPT0B098, could be a promising treatment for cancers. This thesis found that the SOCS family plays a pivotal role in oral cancer. We also found a new possible SOCS regulation pathway in these two studies that can help us to understand the effects of other factors (drug or miRNA) on SOCS cell signaling-related reactions, including migration, invasion and cell proliferation.

關鍵字(中)

★ 口腔癌
★ 微小核醣核酸
★ 細胞因子信號轉導抑制因子
★ 微管蛋白抑製劑

關鍵字(英)

★ Oral cancer
★ MicroRNA
★ Suppressors of cytokine signaling
★ Microtubule inhibitor

論文目次

Table of Contents
Declaration I
Publications arising from this thesis II~ III
(A) Referred papers:
(B) Abstracts presented in meetings:
中文摘要 IV~V
Abstract VI ~ VII
Acknowledgments VIII~IX
Table of Contents X~ XIV
Figure Contents XIII
Figure Contents XIV
Abbreviations XV
Chapter One: Introduction 1~11
1-1 Oral cancer 1~2
1-2 SOCS Regulation of the JAK/STAT Signaling Pathway 2~4
1-3 MicroRNAs and miRNA regulation of SOCS 5
1-4 Cytokines regulates microRNAs 6
1-5 Microtubules and tubulin inhibitors 6~9
1-6 Tubulin inhibitors and STAT3 of study 9~10
1-7 Down-regulation of Stat3 induces apoptosis 10~11
Chapter Two: Specific aims 12~13
Chapter Three: Materials and methods 14~26
3-1 Clinical samples and clinicopathological characteristics 14
3-2 Immunohistochemistry 14~15
3-3 Cell lines and culture condition 15~16
3-4 Culture and Storage of Human Oral Keratinocytes 16~17
3-5 RNA extraction and Reverse-Transcriptase PCR (RT-PCR) 17~18
3-6 Quantitative Real-Time PCR (qRT-PCR) 18
3-7 Plasmids 18~19
3-8 Transfection experiments 19~20
3-9 Protein extraction and western blot analysis 20~21
3-10 Luciferase Reporter Assays 21
3-11 Cell Migration and Invasion Assay 21~22
3-12 Preparation of monomer and polymer fractions of microtubule 22
3-13 Cell viability assay 23
3-14 Cell cycle analysis 23
3-15 Apoptosis assay 23~24
3-16 Immunofluorescent staining and microscopy 24
3-17 Cytokines treatment 25
3-18 Immunoprecipitations 25
3-19 Statistical analysis 25~26
Chapter Four: Result 27~77
4-1 IL8 Induces miR-424-5p Expression and Modulates SOCS2/STAT5 Signaling Pathway in Oral Cancer 27~53
Rationale 27~29
4-1-1 GSEA showed that KEGG Chemokine and/or cytokines and/or JAK/STAT 29
4-1-2 Downregulation of SOCS2 in human OSCC in comparison with adjacent non-tumor tissues 29~30
4-1-3 SOCS2 mediates cellular functions through STAT5 inhibition 30~31
4-1-4 SOCS2 is a direct target of miR-424-5p 31~32
4-1-5 miR-424-5p promotes OSCC cell invasion and migration through direct inhibition of SOCS2 expression 32~33
4-1-6 IL-8 induce miR-424-5p expression through activation of STAT5 33~34
4-1-7 IL-8 promotes OSCC cell invasion and migration through direct induction of miR-424-5p 35
Table and Figure 36~53
4-2 MPT0B098, a microtubule inhibitor, suppresses JAK2/STAT3 signaling pathway through modulation of SOCS3 expression in oral squamous cell carcinoma 54~77
Rationale 54~55
4-2-1 MPT0B098 inhibits the proliferation and tubulin polymerization in OSCC cells
55~56
4-2-2 MPT0B098 induces cell cycle arrest and apoptosis in OSCC cells 56~57
4-2-3 MPT0B098 down-regulates the protein level and activity of JAK2, TYK2 and STAT3 protein 57~58
4-2-4 MPT0B098 down-regulates JAK2, TYK2 and STAT3 through SOCS3 negative feedback modulation 58~59
4-2-5 MPT0B098 promotes SOCS3 binding to JAK2 and TYK2 59~60
4-2-6 MPT0B098 in combination with cisplatin or 5-FU significantly induces apoptosis in OSCC cells 60~61
Table and Figure 62~77
Chapter Five: Discussion 78~84
Chapter Six: General discussion and future work 85~93
Chapter Seven: References 94~117
Appendix: Experimental Drug of formulation 118~121

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指導教授

夏興國、金秀蓮(Shine-Gwo Shiah Shiow-Lian Catherine Jin)

審核日期

2016-7-25

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