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研究生:蔡婉琪
研究生(外文):Wan-Chi Tsai
論文名稱:探討S100A2在口腔上皮細胞癌中的腫瘤抑制功能
論文名稱(外文):The study of S100A2-mediated tumor suppression in oral squamous cell carcinoma
指導教授:吳梨華
指導教授(外文):Li-Wha Wu
學位類別:博士
校院名稱:國立成功大學
系所名稱:基礎醫學研究所
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:2006
畢業學年度:95
語文別:英文
論文頁數:118
中文關鍵詞:口腔癌腫瘤抑制基因
外文關鍵詞:S100A2oral cancertumor suppressor
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在全球,口腔癌是一種相當常見的癌症。雖然有關它的致癌危險因子已經相當清楚,但對於導致口腔癌的分子機轉仍然不甚了解。為了找出因嚼食檳榔而引起的口腔癌所影響的基因,我們利用生物晶片分析十位具有嚼食檳榔習慣的口腔癌病人的1177個基因。在其中,共有84個涉及細胞附著,細胞型態,生長,凋亡,血管新生,腫瘤轉移以及生長代謝的基因表現異常。而這些異常的基因表現與臨床口腔癌分期並無顯著相關。其中,STAT-1,caspase-1以及COX-2在癌前病灶中的過度表現暗示了它們的基因可能早在口腔癌化的初期便已失控因而導致口腔癌的發生。為了更進一步找出口腔癌化過程中表現異常的基因,我們利用更大規模的基因晶片比對兩株由台灣口腔癌病人所建立的口腔癌細胞與正常口腔上皮的基因表現。在7500個基因中,我們發現了S100A2的明顯異常。它在癌細胞中的表現量大約只有正常口腔上皮的三分之一。雖然S100A2在過去被認為是腫瘤抑制基因,但對於它如何發揮抑制腫瘤的功能並不清楚。我們發現S100A2在十株口腔癌細胞中的表現量顯著少於在正常口腔上皮中的表現。因此,我們將S100A2大量表現在上皮細胞癌中並建立成細胞株。我們發現,當細胞大量表現S100A2基因時,細胞的生長,移行以及侵略性都受到明顯的抑制。細胞在低硬度凝膠中形成聚落的能力也大幅降低;更有甚者,S100A2過度表現的細胞在裸鼠皮下形成腫瘤的能力也較弱。而這樣的腫瘤抑制功能我們認為是透過了抑制COX-2的基因表現而達成。重新將COX-2大量表現回原本受到S100A2存在而被抑制的細胞中,能夠部份拮抗掉S100A2所發揮的腫瘤抑制效果。另一方面,利用甲基化以及乙醯化抑制劑,並不能使我們所檢驗的所有口腔癌細胞株中表現量下降的S100A2重新表現。因此,不同於過去的報告,我們認為甲基化以及乙醯化並不是唯一調控S100A2基因的上游機轉。此外,藉由分析S100A2的序列,我們發現在核?酸序列182號位置存在鳥嘌呤/腺嘌呤的多型性。而這樣的核?酸改變會導致胺基酸的不同(天門冬醯胺/絲氨酸)。然而,藉由功能性分析,我們發現,S100A2的多型性並不影響其基因的表現或抑制腫瘤的功能。綜合我們的發現,我們證明了S100A2在口腔癌細胞中扮演了腫瘤抑制基因的角色;並且部份藉由抑制COX-2的表現而發揮其腫瘤抑制的功能。
Oral cancer is one of the most common types of human cancer in the world. Although the risk factors for oral cancer are well-recognized in different countries, the molecular mechanism responsible for this malignancy remains elusive particularly in the countries where betel quid chewing is prevalent. To clarify the genes involved in the oral cancer, especially in patients with betel-quid chewing habit, the cDNA microarray analysis was used to analyze the mRNA expression patterns of 1177 genes in ten oral cancer patients with betel quid chewing history. Eighty-four genes involving cell adhesion, cell shape, growth, apoptosis, angiogenesis, metastasis, and metabolism were deregulated. Although the expression profile of these genes was shared by certain clinical patients, there was no significant association of the expression profile with clinical staging. Overexpression of STAT-1, caspase-1 and COX-2 in the precancer lesions, suggesting that deregulation of these genes might occur early even before malignancy occurred. To further dig out the deregulated genes in oral carcinogenesis, larger scale cDNA microarray was used to screen 7500 human cDNA clones for genes differentially expressed in two Taiwanese oral cancer lines, OEC-M1 and OC-2, compared to normal oral keratinocytes (NOK). The expression level of S100A2 in oral cancer cell lines was found to be only one-third of that in NOK. Although S100A2 is considered a putative tumor suppressor due to its loss or down-regulation in several cancer types, no mechanism has been described for the tumor suppressor role of S100A2. To clarify this role, we employed stable clones of squamous cell carcinoma (SCC) ectopically expressing S100A2. The ectopic expression of S100A2 resulted in a significant inhibition of proliferation, migration, and invasion of cancer cells. Moreover, S100A2 significantly reduced the number of colonies (≧0.5 mm) formed in semisolid agar and decreased the growth of tumor burden in nude mice. Moreover, we found that such potent anti-tumor role of S100A2 in squamous cell carcinoma was partly via reduced expression of COX-2. By the study of epigenetic mechanisms, we found the disagreement from previous studies. The restoration of S100A2 expression by 5’-azaC and/or TSA treatment was not found in every cancer cell line we examined. It implies that there are still other upstream regulatory mechanisms other than methylation and deacetylation for regulating the expression of S100A2. By sequencing the coding region of S100A2, we found a G/A polymorphism in nucleotide 182 of S100A2 that results in asparagines substitution of serine in oral squamous cell carcinoma. No strict correlation in the genotype of S100A2 and the mRNA expression or the tumor suppression role of S100A2 in vitro could be identified. Together, S100A2 indeed behaves as a tumor suppressor partly via repression of COX-2. More studies are needed to examine if other proteins or signaling pathways are involved in the anti-tumor effect of S100A2.
Contents ------------------------------------------------------------------------------- 7
Abbreviation ------------------------------------------------------------------------------- 12
Introduction ------------------------------------------------------------------------------- 13
I. Oral cancer ---------------------------------------------------------------------- 13
General introduction ------------------------------------------------------ 13
Clinical presentation ------------------------------------------------------ 13
Diagnosis and treatment ------------------------------------------------------ 13
Prognosis ------------------------------------------------------------------------ 14
Risk factors for oral cancer ------------------------------------------------------ 14
Tobacco use --------------------------------------------------------------- 14
Alcohol consumption ------------------------------------------------------ 15
Betel-quid chewing --------------------------------------------------------------- 15
Molecular genetics --------------------------------------------------------------- 15
Genetic aberrations --------------------------------------------------------------- 16
p53 ------------------------------------------------------------------------ 16 CD44 ------------------------------------------------------------------------ 16
COX-2 ------------------------------------------------------------------------ 17
EGFR ------------------------------------------------------------------------ 17
Chromosomal imbalances ------------------------------------------------------ 18
II. S100 proteins ------------------------------------------------------------------------ 18
Structure ------------------------------------------------------------------------ 18
Members ------------------------------------------------------------------------ 19
Cellular functions --------------------------------------------------------------- 19
Intracellular functions ------------------------------------------------------ 19
Inhibition of protein phosphorylation ------------------------------------ 19
Regulation of enzyme activity --------------------------------------------- 20
Regulation of cell growth and differentiation --------------------------- 20
Regulation of Ca2+ homeostasis --------------------------------------------- 20
Correlation with the cytoskeleton --------------------------------------------- 21
Extracellular functions ---------------------------------------------------- 21
Target protein binding ---------------------------------------------------- 21
Ca++-dependent ------------------------------------------------------------- 22
Ca++-independent ------------------------------------------------------------- 22
Association with human diseases ------------------------------------------- 23
III. S100A2 ---------------------------------------------------------------------- 24
Historical background ---------------------------------------------------- 24 Alteration of subcellular localization ---------------------------------- 24
Regulation of S100A2 gene expression ---------------------------------- 25
Specific Aims ------------------------------------------------------------------------------- 26
Materials ------------------------------------------------------------------------------- 27
Methods ------------------------------------------------------------------------------- 30
Results ------------------------------------------------------------------------------- 39
I. cDNA microarray analysis of 10 oral cancer patients ------------------------- 39
1. Differential expression of genes in oral cancer ------------------------- 39
2. Correlating the expression patterns of 84 genes with clinical stages ------- 39
3. Validation of 4 deregulated genes in different subsets of clinical specimens 40
II. S100A2 as a tumor suppressor ---------------------------------------------------- 40
1. Decreased expression of S100A2 mRNA in oral cancer lines ---------------- 40
2. Ectopically expressed S100A2 attenuated cellular growth via delayed entry into G2-M
phase ------------------------------------------------------------------------------- 41
3. Ectopic expression of S100A2 reduced cell motility and invasive ability 42
4. S100A2 reduces colony size in vitro and tumorigenesis in vivo ------- 42
5. The suppression effects of S100A2 in nasal septum squamous carcinoma cells 42
6. S100A2 reduced the mRNA and protein expression of COX-2 ------- 43
7. COX-2 caused partial loss of S100A2-mediated anti-tumor effects ------- 43
8. The inverse correlation between S100A2 and COX-2 in clinical oral cancer patients
9. The potential regulators involve in S100A2-mediate cox-2 suppression 45
S100A2 could not act as a transcription factor to regulate cyclin D1 or COX-2 gene
Impaired activated phosphorylation of ERK1/2 by S100A2 ----------------- 45
Transient transfection with constitutive active MKK1 confirms that the inhibition of
COX-2 by S100A2 may not through the MKK-ERK pathway ---------------- 46
Impaired activation of EGFR in S100A2-expressing stable clones ------- 46
III. Methylation status of S100A2 promoter ---------------------------------- 47
1. The effect of 5’-azaC and/or TSA treatments on S100A2 mRNA expression 47
IV. S100A2 polymorphism in the protein coding sequence ---------------- 47
1. The sequence validation of S100A2 coding sequence ---------------- 47
2. The functional difference between wild-type S100A2 and G182A polymorphism 48
Discussions ------------------------------------------------------------------------------- 50
The mRNA profile of genes in betel quid chewing oral cancer patients ------- 50
Cyclooxygenase-2 is involved in S100A2-mediated tumor suppression in squamous cell
carcinoma ------------------------------------------------------------------------------- 52
The possible mechanisms involved in the suppression of COX-2 by S100A2 54
Transcriptional regulator ------------------------------------------------------------- 54
MAPK pathway ---------------------------------------------------------------------- 54
Crosstalk via EGFR1 tyrosine dephosphorylation ------------------------- 54
The tumor suppression effects of S100A2 ------------------------------------------- 55
Attenuation of growth rate without induction of apoptosis ---------------- 55
Inhibition of invasiveness ------------------------------------------------------------- 56
Suppression of migration ability ---------------------------------------------------- 56
The effects of polymorphism on biological functions of S100A2 ---------------- 57
Conclusion ------------------------------------------------------------------------------- 59
Publications ------------------------------------------------------------------------------- 60
References ------------------------------------------------------------------------------- 61
Tables and Figures
Table 1. Clinical data for the study participants ---------------------------------- 77
Table 2. List of 29 genes with decreased expression in oral cancer specimens 78
Table 3. List of 55 genes with increased expression in oral cancer specimens 79
Table 4. S100A2 status in oral cancer cell lines ---------------------------------- 80
Figure 1. Hierarchical clustering of the gene expression data in 10 clinical patients 81
Figure 2. Association of the expression profiles of 84 genes with clinical staging of patient
1– 10 ---------------------------------------------------------------------- 83
Figure 3. Validation of the expression pattern of STAT-1 and caspase-1 by Northern blotting
Figure 4. Validation of COX-2 and pleiotrophin by semi-quantitative RT-PCR 85
Figure 5. Diminished expression of S100A2 mRNA in oral cancer cell lines 86
Figure 6. Levels of S100A2 protein in stable clones and their effects on cellular growth 87
Figure 7. Stalling of S phase by ectopically expressed S100A2 ---------------- 89
Figure 8. Attenuation of the migration and invasion ability of KB cells on S100A2
overexpression ------------------------------------------------------------- 90
Figure 9. Decreased in vitro and in vivo tumorigenicity by ectopically expressed S100A2
Figure 10. The suppression effect on cell growth, invasion, and colony forming ability on
soft agar by S100A2 was also observed in RPMI 2650 cells -------- 95
Figure 11. Functional categories of genes that are significantly altered by S100A2 97
Figure 12. Validation of the expression pattern of COX-2, Cyclin D1 and Thrombomodulin
in control and S100A2-expressing KB cells -------------------------- 98
Figure 13. Partial restoration of growth retardation of S100A2-expressing cells by
reintroduction of COX-2 cDNA ----------------------------------- 99
Figure 14. Partial restoration of malignant behaviors of S100A2-expressing cells by
reintroduction of COX-2 cDNA ----------------------------------- 101
Figure 15. Partial restoration of tumorigenesis in vivo of S100A2-expressing cells by
reintroduction of COX-2 cDNA ----------------------------------- 102
Figure 16. Immunohistochemical staining showed the inverse correlation of S100A2 and
COX-2 in clinical specimens -------------------------------------------- 105
Figure 17. Luciferase reporter assay to measure the transcription factor potential of S100A2
Figure 18. Impaired activation of ERK1/2 in S100A2-expressing KB cells 109
Figure 19. Transient transfection of certain mutated form of ERK2 and/or MKK1 to
demonstrate the upstream regulation of COX-2 by S100A2 -------- 111
Figure 20. Impaired activation of EGFR in S100A2-expressing stable clones 112
Figure 21. 5’-azaC and TSA treatment caused differential effects on S100A2 gene
expression in 10 oral cell lines -------------------------------------------- 113
Figure 22. Sequence of S100A2 surrounding the 182G/A polymorphism -------- 114
Figure 23. Levels of S100A2 in wild-type S100A2 and G182A polymorphism stable clones
Figure 24. The expression of wild-type or G182A polymorphism S100A2 could
significantly attenuate the cell growth ----------------------------------- 116
Figure 25. The effects on invasion and colony forming ability on soft agar of KB cells
overexpressed wild-type or polymorphism form of S100A2 -------- 117
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