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研究生:潘弘偉
研究生(外文):Hung-Wei Pan
論文名稱:L2DTL在肝細胞癌之角色
論文名稱(外文):Role of L2DTL in hepatocellular carcinoma
指導教授:許輝吉許輝吉引用關係
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:病理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
畢業學年度:95
語文別:英文
論文頁數:124
中文關鍵詞:L2DTL細胞週期DNA合成中心粒腫瘤早期復發
外文關鍵詞:L2DTLcell cycleDNA synthesiscentrosomeearly tumor recurrence
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L2DTL是果蠅lethal (2) denticleless (Drosophila lethal (2) denticleless) 基因在人類的同源基因。這個研究主要是為了闡明這個基因在肝細胞癌 (Hepatocellular carcinoma; HCC)腫瘤進行中的功能及與臨床病理間的相關性。我們使用RT-PCR、免疫染色 (immunostaining)、Western blotting、以及中心粒 (centrosome)分離等方法來偵測L2DTL的mRNA表現與蛋白在細胞內的位置,並且利用RNA干擾 (RNAi) 來分析L2DTL在腫瘤細胞生長的角色。

L2DTL mRNA在277個單發性肝細胞癌 (unifocal primary HCCs ) 中有160個 (57%) 是過度表現的,而有這樣過度表現的肝細胞癌,病人年齡較輕 (≧55 歲,p<0.001)、血液中較常見高胎兒蛋白 (AFP >200 ng/mL,p<0.0001),且腫瘤較大(>5 cm,p<0.00001)、分級較高 (grade II-IV, p<0.000001)、分期較高 (stage IIIA-IV,p<0.000001),而且五年存活率較差 (p=0.000001)。為了驗證這樣的相關性,我們將病人隨意均分成兩組,學習組 (139 例),測試組 (139 例),經分析後,上述的相關性在這兩組中依然具有相同的統計意義。在多變量的分析當中,我們發現L2DTL 的過度表現與腫瘤的高分期有非常強的關係,而高分期通常是組織病理上分辨預後不良的最重要決定因子,因此,在病人的預後估計上,L2DTL 過度表現無法成為一個與腫瘤分期無關的獨立因子 (stage-independent prognosticfactor)。進一步分析,肝細胞癌的病人若發生腫瘤早期復發 (early tumor recurrence;ETR),其五年存活率不及10%,遠比那些沒有發生ETR 的病人差 (65%,p=1x10-8)。我們發現L2DTL 過度表現也與病人的ETR 有很強的相關性,而且經由多變量分析,可以知道L2DTL 的過度表現會是一個非常顯著的預測因子。此外,L2DTL 的表現和肝細胞癌病人存活率之間的關係,與p53 基因突變的有無亦有密切的關連。有p53 突變的肝細胞癌中,L2DTL 過度表現的病人其十年存活率較差;但在p53 沒有突變的肝細胞癌中,L2DTL 的過度表現與否,其十年存活率沒有差別。

由雙重免疫螢光染色 (double immunofluorescence staining) 發現L2DTL 蛋白除表現在細胞核外,也會與γ-tubulin 以及Aurora-A 共同表現在中心粒。在細胞週期的進行中,L2DTL 蛋白會一直存在於中心粒上,並且可以藉由層析法得知L2DTL 蛋白會與γ-tubulin 蛋白存在相同的層析中。L2DTL 基因會在細胞週期中的G1/S 時期,或是肝細胞再生 (liver regeneration) 時的DNA 合成時期,其表現量會增加。而L2DTL 蛋白會在細胞分裂 (mitosis) 時期經由APC/C-Cdh1 複合體(APC/C-Cdh1 complex) 的蛋白降解作用使得蛋白質量下降。而L2DTL 的蛋白表現下降也會在HepG2 與NT2 細胞誘發分化的時後發生。而經由L2DTL RNAi oligos所引起的L2DTL 表現下降,則會使得腫瘤細胞在活體與非活體的生長能力下降。經由microarray 的分析,這些經由L2DTL RNAi oligos 處理後的腫瘤細胞中會導致一些與細胞週期調節、DNA 合成、DNA 修復、染色體分隔 (chromosomesegregation) 與細胞分裂相關的基因表現下降。

總結來說,L2DTL 的過度表現與肝細胞癌的進行與轉移能力有關,而且與p53 突變有協力作用,使得有L2DTL 的過度表現的肝細胞癌惡性度更高,且預後更差。在本報告中,我們也第一次指出,L2DTL 這個核蛋白在整的細胞週期進行中,會是一個中心粒蛋白的新成員。在肝細胞癌中,L2DTL 的過度表現與較大的腫瘤與高期別,特別是具血管侵犯能力的腫瘤與較差的預後有關,而降低L2DTL 的表達確實可以抑制腫瘤細胞生長。這樣的結果增加L2DTL 成為腫瘤治療標靶的可能性。我們結論,L2DTL 在DNA 合成、修復、染色體分隔、細胞分裂與中心粒的功能都扮演重要且多面向的角色。基於它在調控細胞週期的進行有
多重重要的功能,也因為如此,干擾L2DTL 的表現會引起腫瘤細胞分裂失敗,以致生長降低更重要的是,當兩個同源染色體上的L2DTL 基因被惕除時,會使得鼠胚胎細胞無法發育導致死亡。
L2DTL is a human ortholog of Drosophila lethal (2) denticleless, l(2)dtl. This study is to elucidate its function and clinicopathological significance in hepatocelllular carcinoma (HCC) progression. We used RT-PCR, immunostaining, Western blotting, and centrosome isolation to determine the L2DTL expression and protein localization. RNAi was used to analyze its role in tumor cell growth.

The L2DTL mRNA was overexpressed in 160 (57%) of 277 unifocal primary HCCs, and the overexpression was associated with younger patient age (≧55 years, p<0.001), high serum AFP (>200 ng/mL, p<0.0001), bigger tumor (>5 cm, p<0.00001), high-grade (grade II-IV, p<0.000001), higher-stage (stage IIIA-IV) HCC (p<0.000001), and lower 5-year survival (p=0.000001). For verification, the patients randomly divided to two groups, the learning (139 cases) and test sets (138 cases). These correlations were confirmed in both sets of patients. Multivariate analysis showed that L2DTL overexpression strongly correlated with tumor stage, which was the most crucial unfavorable histopathological prognostic factor, and hence was not a stage-independent prognostic factor. Further, HCC patients with early tumor recurrence (ETR) had a 5-year survival less than 10% as compared with those without ETR above 65%, p=1x10-8. L2DTL overexpression strongly correlated with ETR and was a significant predictor for ETR after multivariate analysis. L2DTL overexpression correlated with poor progonosis and closely associated with p53 mutation. Moreover, in the p53-mutated HCCs, a concomitant L2DTL overexpression was associated with a lower 10-year survival (p=0.00006), as compared with p53-mutated HCC without the overexpression in the subset of HCCs without p53 mutaion, there was no significant difference in ten-year survival in HCC with and without L2DTL overexpression.

Using the double immunofluorescence staining, L2DTL protein located to the nucleus in interphase and centered to centrosomes, with co-localization of γ-tubulin
and Aurora-A, throughout the cell cycle, and co-fractionated with γ-tubulin. L2DTL gene expression increased during G1/S phase in cell cycle, and the period of DNA sysnthesis in liver regeneration. L2DTL protein decreased in mitosis via degradation by the APC/C-Cdh1 complex. L2DTL was downregulated in the induced
differentiation of HepG2 and NT2 cells. L2DTL downregulation by RNAi oligos led to reduced cancer cell growth in vivo and in vitro, in which microarray analysis
disclosed dysregulation of genes involved in cell cycle regulation, DNA synthesis, DNA repair, chromosome segregation, and cell division.

In conclusion, L2DTL overexpression is associated with enhanced metastatic potential of HCC, and contributes synergistically with p53 mutation toward advanced HCC with poor prognosis. In this report, we show for the first time that the nuclear L2DTL protein is also a novel component of the centrosome proteins throughout the cell cycle and participates in cell cycle progression. L2DTL overexpression in HCC is associated with bigger size tumor and high tumor stage, particular portal vein invasion, and poor prognosis, whereas the RNAi knockdown is associated with suppression oftumor cell growth. These findings raise the possibility that L2DTL may be a noveltherapeutic target. We conclude that the L2DTL plays important multi-faceted roles inDNA synthesis, DNA repair, chromosome segregation, cell division and centrosomelocalization. Base on its crucial multiple functions in the control of cell cycle progression, the L2DTL expression contributed to cancer cell growth, whereas its downregulation led to reduce tumor cell growth, chromosome segregation andcytokinesis failure. Importantly, its homozygous knockout in mice leads to very earlyembryonic lethality.
1. 中文摘要 -------------------------------------------------------------- 1

2. ABSTRACT ------------------------------------------------------------ 3

3. GENERAL INTRODUCTION ------------------------------------ 6
3.1 Review of Hepatocellular Carcinoma (HCC) ----------------------------- 6
3.1.1 Pathogenesis of HCC ------------------------------------------------------- 6
3.1.1.1 Chronic hepatitis and cirrhosis --------------------------------------- 8
3.1.1.2 Aberrant genetic changes of hepatocellular carcinoma --------- 9
3.1.1.3 Tumor suppressor genes and oncogenes ---------------------------- 9
3.1.2 Recurrence and Prognosis ------------------------------------------------- 10
3.1.3 Prognostic molecular markers of HCC --------------------------------- 10
3.2 Cell Cycle and Cancer --------------------------------------------------------- 11
3.2.1 The cell cycle ----------------------------------------------------------------- 11
3.2.2 Deregulation of cell cycle regulators and cancer --------------------- 12

4. THE REASONS AND SPECIFIC AIMS ABOUT THE LAUNCHING OF PRESENT STUDIES ------------------------
14

5. SPECIFIC AIMS OF THIS STUDY ------------------------------ 15

6. MATERIALS AND METHODS ----------------------------------- 16
6.1 Patients ---------------------------------------------------------------------------- 16
6.2 Histologic study, tumor staging, early tumor recurrence (ETR), and treatment -------------------------------------------------------------------------
16
6.3 p53 mutation and Follow-up observation ---------------------------------- 17
6.4 Statistical analysis --------------------------------------------------------------- 17
6.5 The predictions of L2DTL protein using the bioinformation tools -- 18
6.6 Differential display (DD), reverse transcription-polymerase chain reaction (RT-PCR), and definition of L2DTL overexpression --------
18
6.7 Plasmid, transient transfection and cell lines ----------------------------- 19
6.8 Antibodies ------------------------------------------------------------------------ 20
6.9 Generation of anti-L2DTL antibodies -------------------------------------- 20
6.10 Immunoprecipitation and Western blot of nuclear and cytosolic protein fractions --------------------------------------------------------------- 20
6.11 Immunofluorescence and immunohistochemical stains --------------- 21
6.12 Cell synchrony and cell cycle distribution ------------------------------- 21
6.13 Isolation of centrosomes ----------------------------------------------------- 22
6.14 Cell differentiation ------------------------------------------------------------ 22
6.15 Mouse liver regeneration ---------------------------------------------------- 22
6.16 Yeast two-hybrid screen ------------------------------------------------------ 23
6.17 RNA interference (RNAi) and L2DTL knockdown -------------------- 23
6.18 Cell proliferation, anchorage-independent growth, and in vitro cell invasion ------------------------------------------------------------------------- 24
6.19 Tumorigenicity Assay -------------------------------------------------------- 25
6.20 RNA isolation and microarray analysis ---------------------------------- 25

7. RESULTS -------------------------------------------------------------- 27
7.1 Section 1: Overexpression of L2DTL is associated with advanced hepatocellular carcinoma and predicts early tumor recurrence (ETR) and synergism with p53 mutation toward poor prognosis -----27
7.1.1 L2DTL mRNA expression in fetal and adult tissues, and multiple cancers ------------------------------------------------------------------------27
7.1.2 L2DTL expression in relation to major clinicopathological features of HCC and validation in learning and test sets of patients ------------------------------------------------------------------------27
7.1.3 L2DTL overexpression and clinical outcomes ------------------------- 28
7.1.4 L2DTL overexpression and major histopathologic factors in relation to ETR --------------------------------------------------------------29
7.1.5 L2DTL overexpression is the most risk molecular factor in ETR and progonosis in HCC ----------------------------------------------------30
7.1.6 L2DTL expression in prediction of ETR of low-stage HCC ----- 31
7.1.7 Synergistic effects of L2DTL overexpression and p53 mutation in HCC progression and poorer prognosis -------------------------------31

7.2 Section 2: Overxpression of L2DTL, Encoding a Cell Cycle Regulated Nuclear and Centrosome Protein Involved in Cell Proliferation, Correlates with Aggressive Hepatocellular Carcinoma -----------------------------------------------------------------------33
7.2.1 The features of L2DTL protein ------------------------------------------- 33
7.2.1.1 L2DTL protein ----------------------------------------------------------- 33
7.2.1.2 The expression profile of L2DTL ------------------------------------- 33
7.2.1.3 The features of L2DTL protein --------------------------------------- 34
7.2.2 Nuclear expression of L2DTL protein in culture cells and HCC tumor cells --------------------------------------------------------------------- 36
7.2.3 L2DTL expression during cell cycle progression and Cdh1-mediated degradation -----------------------------------------------37
7.2.4 L2DTL as a novel centrosome protein throughout cell cycle ------- 38
7.2.5 L2DTL expression in tumor cell differentiation and liver regeneration ------------------------------------------------------------------- 38
7.2.6 Down-regulation of L2DTL reduced in vitro tumor cell growth ---- 39
7.2.7 Down-regulation of L2DTL reduced in vitro tumor cell invasion --- 40
7.2.8 Downregulated of L2DTL by RNAi oligos led to increase in bi- and multi-nucleated cells --------------------------------------------------- 40
7.2.9 Downregulation of L2DTL expression led to aberrant expressions of genes involved in cell cycle progression, DNA replication, chromosome segregation, and cell division ------------------------------40

7.3 Supplement results --------------------------------------------------------------- 42
7.3.1 The yeast two-hybrid screen ------------------------------------------------ 42
7.3.2 Stable Knockdown of L2DTL by siRNA reduced the anchorage-independent growth and tumor formation in the NOD/SCID Mice -------------------------------------------------------------- 43
7.3.3 Wound-healing migration assay ------------------------------------------- 43

8. DISCUSSION --------------------------------------------------------- 44
8.1 The pathological contribution of L2DTL ---------------------------------- 44
8.1.1 Correlation with aggressive HCC and lead to poor progonosis --- 44
8.1.2 L2DTL is a predictor for early tumor recurrent (ETR) ------------ 45
8.1.3 L2DTL overexpression contributes synergistically with p53 mutation toward advanced HCC --------------------------------------- 46
8.2 The biological roles of L2DTL ----------------------------------------------- 48
8.2.1 Cell proliferation and differentiation ----------------------------------- 48
8.2.2 Distribution in cell cycle --------------------------------------------------- 49
8.3 The functional roles of L2DTL in cell cycle ------------------------------- 52
8.3.1 Potential role of L2DTL in G1/S phase and DNA synthesis -------- 52
8.3.2. Response during DNA damage ------------------------------------------ 56
8.3.3 The roles involved in chromosome segregation and cell division -- 57
8.3.4 L2DTL as a novel member of centrosome proteins ------------------ 59
8.3.5 The role of cell mobility --------------------------------------------------- 60
8.4 The latest developments of L2DTL research ------------------------------ 62

9. FIGURES -------------------------------------------------------------- 65
Figure 1. Differential Display, expression of L2DTL mRNA in fetus and adult tissues ---------------------------------------------------------------- 65
Figure 2. L2DTL mRNA expression in HCCs ----------------------------------- 66
Figure 3. L2DTL mRNA expression in cell lines ------------------------------- 67
Figure 4. L2DTL mRNA expression in other liver tumors ------------------- 68
Figure 5. L2DTL expression in hepatocellular carcinoma (HCC) and cumulative survival ------------------------------------------------------ 69
Figure 6. Early tumor recurrence (ETR) and tumor stage in relation to cumulative survival ------------------------------------------------------ 70
Figure 7. L2DTL expression and p53 mutation in relation to cumulative survival ---------------------------------------------------------------------71
Figure 8. The expression profile of L2DTL/ramp from SOURCE website --------------------------------------------------------------------------------72
Figure 9. Genes with the same binary expression profile in HeLa cell as L2DTL ----------------------------------------------------------------------73
Figure 10. The motifs of L2DTL protein ----------------------------------------- 74
Figure 11. The L2DTL protein exhibits cell cycle related features ---------- 75
Figure 12. L2DTL protein expression --------------------------------------------- 76
Figure 13. L2DTL protein subcellular localization ---------------------------- 77
Figure 14. L2DTL expression in cell cycle progression ----------------------- 78
Figure 15. L2DTL protein expression in cell cycle progression and regulation -----------------------------------------------------------------79
Figure 16. Subcellular distribution of L2DTL protein (green) during the cell cycle progression --------------------------------------------------80
Figure 17. Association of L2DTL with the centrosomes across cell cycle progression --------------------------------------------------------------- 81
Figure 18. Centrosome localization of L2DTL protein (red) during the cell cycle progression --------------------------------------------------- 82
Figure 19. L2DTL expression in cell differentiation and liver regeneration -------------------------------------------------------------- 83
Figure 20. L2DTL knockdown by L2DTL RNAi caused suppression of in vitro cell growth --------------------------------------------------------- 84
Figure 21. L2DTL knockdown by L2DTL RNAi caused cell death -------- 85
Figure 22. Colony formation assay ----------------------------------------------- 86
Figure 23. Transwell assay (in vitro invasive assay) --------------------------- 87
Figure 24. L2DTL knockdown by L2DTL by RNAi oligos increased the bi- and multi-nucleated HeLa cells ---------------------------------- 88
Figure 25. Microarray analysis identified dysregulated cell cycle related genes after L2DTL knockdown -------------------------------------- 89
Figure 26. Confirmation of microarray results --------------------------------- 90
Figure 27. The yeast two-hybrid screen, PCNA and L2DTL interaction -------------------------------------------------------------------------------91
Figure 28. siRNA knockdown of L2DTL and tumor cells growth ---------- 92
Figure 29. Wound-healing migration assay ------------------------------------- 93

10. TABLES --------------------------------------------------------------- 94
Table 1. Relation of L2DTL mRNA expression to other baseline characteristics in 277 patients with resected unifocal primary Hepatocellular Carcinoma -----------------------------------------------
94
Table 2. Relation of L2DTL mRNA expression to other baseline characteristics in 277 patients with resected unifocal primary hepatocellular carcinoma ------------------------------------------------- 95
Table 3. Univariate Cox proportional hazards regression of clinical outcomes on L2DTL overexpression and other covariates in 277 patients with resected unifocal primary hepatocellular carcinoma --------------------------------------------------------------------96
Table 4. Multivariate Cox proportional hazards regression of clinical outcomes on L2DTL overexpression and other covariates in 277 patients with resected unifocal primary hepatocellular carcinoma -------------------------------------------------------------------- 97
Table 5. L2DTL expression in relation to early tumor recurrence (ETR) in low-stage hepatocellular carcinoma ---------------------------------
98
Table 6. Synergistic Effects of L2DTL mRNA expression and p53 mutation on tumor progression in 222 patients with resected hepatocellular carcinoma ------------------------------------------------- 99
Table 7. The significant down-regulation genes after loss of L2DTL expression --------------------------------------------------------------------100
Table 8. The significant up-regulation genes after loss of L2DTL expression --------------------------------------------------------------------106

11. REFERENCES ------------------------------------------------------ 109

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