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研究生:丁韋仁
研究生(外文):Wei-Jen Ting
論文名稱:Bad絲胺酸112位點透過高度表達的MAPK p38β磷酸化導致口腔癌產生TNF-α誘導凋亡之抗性
論文名稱(外文):Bad絲胺酸112位點透過高度表達的MAPK p38β磷酸化導致口腔癌產生TNF-α誘導凋亡之抗性
指導教授:黃志揚黃志揚引用關係
學位類別:博士
校院名稱:中國醫藥大學
系所名稱:基礎醫學研究所博士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:72
中文關鍵詞:口腔癌鱗狀細胞癌p38β促分裂原活化蛋白激酶(p38α MAPK)腫瘤壞死因子α(TNF-α)Bad絲胺酸112位點(Badser112)
外文關鍵詞:oral cancerSCCp38β MAPKTNF-αBadser 112
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臺灣的口腔癌患者三年存活率約為58%,在經過腫瘤切除手術後的三年存活率則可以增加到74%。在人類的口腔鱗狀細胞癌(squamous-cell carcinoma,SCC)的發展過程,長時間的發炎症狀的組織切片中經常發現有表皮生長因子(epidermal growth factor,EGF)的過度表達的情況,EGF可以經由活化其表皮生長因子受體(epidermal growth factor receptor, EGFR)誘導鱗狀細胞癌的細胞增生。另外,發炎過程的所釋放的腫瘤壞死因子(tumor necrosis factor,TNF-α)也失去了原有的抗腫瘤作用,因此在許多口腔癌病患中也可以發現具有TNF-α抗性的腫瘤。在本研究中,使用4-硝基????1-氧化物(4-nitroquinoline 1-oxide,4-NQO)誘導C57B小鼠舌?N狀細胞株T28與人類舌?N狀細胞株SCC4中均發現具有TNF-α抗性,另外還有p38β促分裂原活化蛋白激?﹛]mitogen-activated protein kinases,MAPK)的高度表達。同樣的,在超過40%以上的人類口腔癌組織陣列樣本中也有p38β MAPK高度表達的現象。由於p38 MAPK調控TNF-α的釋放,所以T28和SCC4細胞株的TNF-α抗性也懷疑與p38β MAPK的表現有高度的關聯性。本研究發現口腔癌細胞中的B細胞淋巴瘤-2基因相關細胞凋亡促進蛋白(Bcl-2-associated death promoter,Bad)絲胺酸136位點的磷酸化是由p38α MAPK所調控、Bad絲胺酸112與155位點的磷酸化則是由p38β MAPK所調控,而Bad絲胺酸112位點的磷酸化扮演了口腔癌細胞抗凋亡的守門員角色。過度表達p38β MAPK的口腔癌細胞確實通過Bad絲胺酸112的磷酸化產生針對TNF-α誘導的細胞凋亡的耐受性。


In Taiwan, the three-year survival rate of oral cancer patients is only 58% and increases to 74% after surgery. Before human squamous cell carcinoma (SCC) develops, hyperplasia is a symptom of the initial stage that is induced by epidermal growth factor (EGF) over-expression due to long term inflammation and then EGF can activate epidermal growth factor receptor (EGFR) and trigger the SCC proliferation. Tumor necrosis factor-alpha (TNF-α) released in the context of inflammation loses its original anti-tumor function, and TNF-α resistance might occur in many cases. In the current study, TNF-α resistance was confirmed in the 4-nitroquinoline-N-oxide (4-NQO)-induced T28 oral cancer cell line in C57B mice and in the human tongue squamous cell carcinoma cell line, SCC4. The results of the present investigation show that p38β mitogen-activated protein kinases (p38β MAPK) over-expression occurs in more than 40% of SCC in a human tissue array. The release of TNF-α occurs through p38 MAPK, and TNF-α resistance exists in both the T28 and SCC4 cell lines might highly relate to p38β MAPK. MAPK p38β over-expression in oral cancer might be associated with TNF-α resistance through phosphorylation of serine 112 in Bad (Bcl-2-associated death promoter), which is a gatekeeper of Bad-mediated apoptosis. Phosphorylation of serine 136 in Bad was promoted by the p38α MAPK isoform. Phosphorylation of Bad serine 112 and 155 was promoted by p38β MAPK, and phosphorylation of these residues also blocks the apoptosis caused by TNF-α. In conclusion, over-expression of p38β MAPK in oral cancer indeed caused resistance to TNF-α-induced apoptosis through the phosphorylation of Bad serine 112.

Chapter 1 Introduction……………………………………………………………….. 1
1-1 Oral cancer of the world………………………………………………… 1
1-2 Etiology of oral cancer……...…………………………………………... 1
1-3 Animal models in oral cancer research…………………………………. 3
1-4 The expressions and roles of TNF-α in oral cancer…………………….. 5
1-5 Mitogen-activated protein kinases………….…………………………... 6
1-6 Tumor necrosis factor-related apoptosis-inducing ligands……………... 9
1-7 The Bcl-2-associated death promoter (Bad) protein……....................... 11

Chapter 2 Material and methods……………………………………………………. 11
2-1 Immunohistochemistry………………………………..………………. 11
2-2 Cell culture…………………...………………………………………... 12
2-3 MTT assay……....................…………………………………………... 12
2-4 p38 siRNA Transfection Assay………………………………………... 13
2-5 Protein analysis.………………………………………………….……. 13
2-6 Co-Immnunoprecipitation assay………………………………………. 14
2-7 Expression plasmid and cell transfection…...…………………………. 15
2-8 Cell cycle analysis and detection of apoptosis...………………………. 15
2-9 Confocal microscope detection..……...……………………………….. 16
2-10 Animal experiments…..…..….….…………………………………… 16
2-11 Tissue protein extraction.……...……………………………............... 17
2-12 Hemotoxyline and eosin staining…..…..….….……………………… 17
2-13 Masson’s trichrome staining..……...………………………………… 18
2-14 DAPI and TUNEL staining…..…..….….……………………………. 18
2-15 Statistical analysis..…….…………………………………………….. 18
Chapter 3 Results…………………………………………………………………… 19
3-1 p38β MAPK is highly expressed in oral cancer progression………….. 19
3-2 p38 MAPK enhance the oral cancer in animal model cell line ……… 19
3-3 p38β is upregulated in oral cancer cells …………………….………… 19
3-4 p38β deficiency decreases the viability of T28 oral cancer cells ……... 20
3-5 p53 is upregulated in p38β deficient cells …………………………….. 20
3-6 p38β deficiency induces apoptosis in T28 oral cancer cells ………….. 20
3-7 Protein expressions related with cancer cell aggravation………........... 20
3-8 Cell lines proliferation rate …………………………………………… 21
3-9 TRAIL resistance biomarkers in oral cancer cells …………..………... 21
3-10 TRAIL resistance was proved in oral cancer cell lines……………... 21
3-11 p38α and p38β contribute to different Bad phosphorylation residues.. 22
3-12 p38β induced the Badser112 phosphorylation against TNF-α………….. 23
3-13 SB202190 inhibited the p38β and Badser112 phosphorylation ………... 23
3-14 SB202190 induced SCC4 cell cycle arrest …………..…………….... 23
3-15 p38β inhibition reduced T28 xenograft tumors in C57B mice …….... 23
3-16 p38β inhibiton reduced SCC4 xenograft tumors in Narl mice …........ 24

Chapter 4 Discussions………………………………………………………………. 25

Chapter 5 Conclutions………………………………………………………………. 28

References.............………………………………………………………………...... 29

Figures

Figure 1. Incidence of oral cavity cancer (Male)…………………………………….42
Figure 2. Incidence of oral cavity cancer (Female)………………………………… 43
Figure 3. Chemical structures of 4-NQO and its metabolites………………………..44
Figure 4. The signaling pathway of TRAIL-induced apoptosis..………………........ 45
Figure 5. The expression of p38β MAPK in the human tissue array……………….. 46
Figure 6. p38 MAPK enhance the p-EGFR, TNF-α expressions in oral cancer……………………………………… 47
Figure 7. p38β MAPK is upregulated in oral cancer cells………………………….. 48
Figure 8. p38β MAPK deficiency decreases the viability of T28 oral cancer cells… 49
Figure 9. p53 is upregulated in p38β deficient cells....…………………………… 50
Figure 10. p38β MAPK deficiency induces apoptosis in T28 oral cancer cells...….. 51
Figure 11. The proteins expressions in normal/oral cancer cells…………………… 52
Figure 12. The cell proliferation rate in normal/oral cancer cells…………………... 53
Figure 13. TRAIL resistance biomarkers in oral cancer cells………………………. 54
Figure 14. The role of phosphorylated Bad in TNF-α resistance…………………… 55
Figure 15. TNF-α treatment decreased non-tumor cell survival ability…………….. 56
Figure 16. The p38α/βMAPK related Bad phosphorylation………………………... 57
Figure 17. The p38α/βMAPK related Bad phosphorylation.………………………. 58
Figure 18. p38α and p38β contribute to different Bad phosphorylation residues..…. 59
Figure 19. The SB202190 inhibit the p-Badser112 expressions in TNF-α resistance oral cancer cells……………………………………………………………… 60
Figure 20. The SB202190 inhibit the p-Badser112 and p38β expressions in T28 oral cancer cells..……………………………………………………………. 61
Figure 21. The SB202190 inhibit the p-Badser112 and p38β expressions in SCC4 oral cancer cells..……..……………………………………………………… 62
Figure 22. The SB202190 treatments caused a cell cycle arrest in SCC4 cells…….. 63
Figure 23. The p38β MAPK inhibitor treatments reduced the T28 tumor volumes in C57B mice………………………………………………………………. 64
Figure 24. The p38β MAPK inhibitor treatments decreased the p38β and p-Badser112 expressions in the T28 tumor of C57B mice..………………………… 65
Figure 25. The p38β MAPK inhibitor induce cell apoptosis in the T28 tumor of C57B mice………………………………………………………………..…… 66
Figure 26. The p38β MAPK inhibitor treatments reduced the SCC4 tumor volumes in nude mice ...……………………………………………………. 67
Figure 27. The p38β MAPK inhibitor treatments decreased the p38β and p-Badser112 expressions in the SCC4 tumor of nude mice..………………………… 68
Figure 28. The p38β MAPK inhibitor induce cell apoptosis in the SCC4 tumor of nude mice ………………………………………………………………. 69
Figure 29. The p38 MAPK dominate TNF-α release and p38β MAPK expression cause a TNF-α resistance through the downstream Bad phosphorylation..……………………………………………..…………. 70

Tables

Table 1. Molecular biomarkers from human oral cancer tissues.……..……………...71
Table 2. Molecular biomarkers from 4-NQO induce animal oral cancer tissues..…72







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