核醣-5-磷酸異構酶A在大腸直腸癌和肝細胞癌形成中的分子機制

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研究生：	邱于庭 Chou, Yu-Ting
論文名稱：	核醣-5-磷酸異構酶A在大腸直腸癌和肝細胞癌形成中的分子機制 The molecular mechanisms of ribose-5-phosphate isomerase A in the formation of colorectal cancer and hepatocellular carcinoma
指導教授：	喻秋華 Yuh, Chiou-Hwa 汪宏達 Wang, Horng-Dar
口試委員:	楊慕華 Yang, Muh-Hwa 姜正愷 Jiang, Jeng-Kai 吳肇卿 Wu, Jaw-Ching
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物科技研究所 Biotechnology
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	165
中文關鍵詞：	核醣-5-磷酸異構酶A 、大腸直腸癌、肝細胞癌、β-連環蛋白、胞外訊號調節激酶
外文關鍵詞：	Ribose-5-phosphate isomerase A, colorectal cancer, hepatocellular carcinoma, β-catenin, extracellular signal-regulated kinase
相關次數：	點閱：4 下載：0
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新陳代謝的改變是癌症的特徵之一。已知戊糖磷酸途徑中核糖-5-磷酸異構酶A的失調會促進肝，肺和結腸中的腫瘤發生，然而由核糖-5-磷酸異構酶A介導的腫瘤發生分子機制尚不清楚。我們的研究表明（1）核糖-5-磷酸異構酶A在大腸直腸癌中具有非典型功能（2）核糖-5-磷酸異構酶A同時透過β-連環蛋白和pERK信號傳遞誘導肝癌型成（3）核糖-5-磷酸異構酶A在不同癌症類型中其作用具有多樣性。
首先，這些數據表明核糖-5-磷酸異構酶A在結腸癌中顯著升高，其透過在結腸癌細胞中活化β-連環蛋白進而調節細胞增生和促使癌症形成。不同於在細胞質中參與戊糖磷酸途徑的功能，在結腸癌細胞中核糖-5-磷酸異構酶A會進入細胞核並與APC和β-連環蛋白形成複合物。藉由這種保護機制能防止-連環蛋白被泛素化和降解。核糖-5-磷酸異構酶A的C端（胺基酸290至311）是誘導腫瘤發生所必需的重要位置。與體外結果一致，核糖-5-磷酸異構酶A增加β-連環蛋白及其下游基因的表達，隨後誘導轉基因魚中的腸道腫瘤生成。為了進一步研究核糖-5-磷酸異構酶A對於肝癌發生的影響，我們利用肝臟專一表達核糖-5-磷酸異構酶A的轉基因魚，發現具有脂肪堆積進而產生纖維化的現象，到了晚期，更發現有細胞增殖能力上升的趨勢。使用免疫組織化學分析，我們發現核糖-5-磷酸異構酶A過度表達會藉由ERK和β-連環蛋白信號傳導途徑造成肝臟癌化行成。我們注意到核糖-5-磷酸異構酶A可能通過不同的信號傳導調節腫瘤的發生，因此我們分析了十八種不同癌症中的核糖-5-磷酸異構酶A蛋白表現情形。綜合這些研究，我們認為核糖-5-磷酸異構酶A對於癌症的初始或惡化扮演重要角色，透過核糖-5-磷酸異構酶A標靶治療或許能成為一種治療癌症的替代策略。

Altered metabolism is one of the hallmarks of cancers. Dysregulation of ribose-5-phosphate isomerase A (RPIA) in pentose phosphate pathway is known to promote tumorigenesis in prostate, liver and colon. However, the molecular mechanism of RPIA-mediated tumorigenesis is unknown. Our study demonstrates (1) RPIA has a non-canonical function in colorectal cancer (CRC) (2) RPIA induces hepatocellular carcinoma (HCC) through β-catenin and pERK signaling (3) RPIA plays divers role in different cancer types.
First, these data indicate RPIA is significantly elevated in CRC. RPIA modulates cell proliferation and oncogenicity via activation of β-catenin in colon cancer cells. Unlike its role in pentose phosphate pathway (PPP) in which RPIA functions within the cytoplasm, RPIA enters the nucleus to form a complex with APC and β-catenin. This association protects β-catenin by preventing its proteolytic ubiquitination and degradation. The C-terminus of RPIA (AAs 290 to 311) is necessary for RPIA-mediated tumorigenesis. Consistent with results in vitro, RPIA increases the expression of β-catenin and its target genes, subsequent induces tumorigenesis in Tg(ifabp:RPIA;myl7:EGFP) zebrafish. To further investigate RPIA-mediated hepatocarcinogenesis, we found that RPIA overexpression induce steatosis followed by fibrosis. At a later stage, RPIA overexpression enhance the proliferative cells. Using immunohistochemistry analysis, we found RPIA overexpression leads to steatosis, fibrosis and HCC is through both the ERK and β-catenin signaling pathways. We noticed RPIA may regulate tumorigenesis by distinct signaling, hence we analyzed RPIA protein levels in eighteen different cancers. Together, we suggest RPIA may represent valuable targets for therapeutic agents in several cancers.

Abstract    I
中文摘要    II
致謝    III
Content    V
Abbreviation List    XIII
Chapter 1. Introduction    1
Colorectal cancer    1
Hepatocellular carcinoma    2
Pentose phosphate pathway and cancer development    3
Ribose-5-phosphate isomerase A and cancer     4
RPIA in CRC    5
RPIA in HCC    5
Zebrafish as human disease models    6
Chapter 2. Materials and Methods    8
Ethics statement    8
Cell culture    8
Transfection and siRNA interference    8
Plasmid construction and transfection    9
Hematoxylin-eosin (HE) and IHC staining    9
Western blotting, fractionation, and Immunoprecipitation analysis    10
Colony formation assay    10
Reverse transcription and qPCR    11
Luciferase reporter assay    11
Immunofluorescence assay    11
Oil Red O staining    12
Sirius Red Staining    12
Transgenic zebrafish    13
Zebrafish husbandry    14
Chapter 3. Results    15
I. Identification of a non-canonical function for ribose-5-phosphate isomerase A promotes colorectal cancer formation by stabilizing and activating β-catenin via a novel C-terminal domain    15
RPIA is highly expressed in different stages of human CRC tissue    15
RPIA levels are positively correlated with β-catenin protein levels, cellular proliferation, and oncogenicity    16
RPIA-mediated stabilization of β-catenin in colon cancer cells does not involve ERK signaling    18
RPIA forms a complex with β-catenin and APC in both the nucleus and cytoplasm    21
The C-terminal domain of RPIA is necessary for enhanced cell proliferation in colon cancer cells    22
RPIA promotes intestinal tumorigenesis in RPIA transgenic zebrafish in vivo    23
II. Ribose-5-Phosphate Isomerase A (RPIA) Overexpression Promotes Liver Cancer Development in Transgenic Zebrafish via activation of ERK and β-catenin pathways    25
RPIA-overexpression activates lipogenic factor/enzyme expression and causes liver steatosis    25
Effects of RPIA expression on liver fibrosis    26
RPIA mediated induction of cirrhosis is transaldolase independent    27
RPIA-mediated induction of PCNA and cell cycle/proliferation-related markers    28
ERK is activated between seven and eleven months of age in RPIA- transgenic fish    29
β-Catenin is activated in RPIA transgenic fish    29
Examination of histopathological changes in the livers of transgenic RPIA zebrafish by H&E staining    31
Appendix    32
RPIA is positive correlated with β-catenin in lung tissue    32
RPIA and β-catenin have similar expression pattern in prostate and thyroid tissue    32
RPIA has a negative correlation with β-catenin in pancreas tissue    34
β-Catenin expression levels are opposite of RPIA in cervix uteri and kidney tissue    35
Up-regulation of RPIA in cytoplasm and down-regulation of β-catenin in nucleus are observed in uterine cancer    36
RPIA is up-regulated in cancerous testicular tissue    36
β-Catenin is up-regulated in nucleus in skin cancer    37
RPIA is down-regulated in nucleus in brain cancer    38
β-Catenin is down-regulated in cancerous tissue of head and neck and soft tissue    38
Chapter 4. Discussion    40
I. Identification of a noncanonical function for ribose-5-phosphate isomerase A promotes colorectal cancer formation by stabilizing and activating β-catenin via a novel C-terminal domain    40
II. Ribose-5-Phosphate Isomerase A (RPIA) Overexpression Promotes Liver Cancer Development in Transgenic Zebrafish via activation of ERK and β-catenin pathways    45
III. Variant roles of Ribose-5-Phosphate Isomerase A (RPIA) and β-catenin in different cancer types    48
Figures    51
Figure 1. RPIA is highly expressed in different stages of CRC    52
Figure 2. siRNA sequence of RPIA    54
Figure 3. RPIA levels are positively correlated with cellular proliferation.    56
Figure 4.  RPIA levels are positively correlated with colony formation ability.    58
Figure 5. RPIA regulates colon cancer cell proliferation by modulating protein levels of β-catenin.    60
Figure 6. RPIA modulates β-catenin activity and target genes.    62
Figure 7. RPIA modulates β-catenin protein levels in both cytoplasm and nucleus.    64
Figure 8. ERK and EGFR signaling are not involved in the RPIA-mediated colon cancer tumorigenesis.    66
Figure 9. Transketolase (TKL) and Ribose-5-phosphate epimerase (RPE) are not up-regulated by RPIA expression.    68
Figure 10. RPIA expression is positive correlated with β-catenin protein levels in colon tissue or nucleus.    70
Figure 11. Knock down of RPIA decreases β-catenin protein stability in colon cancer cells.    72
Figure 12. RPIA increases β-catenin protein stability in colon cancer cells.    74
Figure 13. RPIA protects β-catenin from proteasomal degradation process.    76
Figure 14. GSK3β is involved in the RPIA-regulated β-catenin signaling.    78
Figure 15. RPIA localizes in the nucleus.    80
Figure 16. RPIA interacts with APC and β-catenin in colon cancer cells.    82
Figure 17. The RPIA amino acid sequence is highly conserved among human, mouse and zebrafish.    84
Figure 18. The mRNA expression level and protein expression pattern of RPIA and its deletion mutants.    86
Figure 19. The C-terminal domain of RPIA containing amino acids 290 to 311 is required for cell proliferation and β-catenin stabilization in colon cancer cells.    88
Figure 20. RPIA induce nuclear atypia, increased nuclear-to-cytoplasmic ratio and up-regulated β-catenin expression in intestinal bulb.    90
Figure 21. RPIA induce nuclear atypia, increased nuclear-to-cytoplasmic ratio and up-regulated β-catenin expression in middle intestine.    92
Figure 22. RPIA induce nuclear atypia, increased nuclear-to-cytoplasmic ratio and up-regulated β-catenin expression in posterior intestine.    94
Figure 23. RPIA promotes β-catenin target genes expression in vivo.    96
Figure 24. The body weight, body width, intestine length and body length in 1-year-old RPIA Tg fish.    98
Figure 25. Model of the RPIA mechanism for induction of β-catenin signaling in CRCs.    100
Figure 26. RPIA expression level has high correlation with HBV(+)-HCC tumor stage from I to III.    102
Figure 27. Lipogenic enzymes and factors are up-regulated in RPIA transgenic fish.    104
Figure 28. RPIA-transgenic fish develops steatosis as early as 3M and 5M RPIA transgenic fish.    106
Figure 29. RPIA transgenic fish develops fibrosis at five and seven months of age.    108
Figure 30. Transaldolase expression level is not affected by the over-expression of RPIA in transgenic zebrafish.    110
Figure 31. RPIA transgenic fish increases expression level of cell cycle markers and PCNA nuclear staining at 9 and 11 months of age.    112
Figure 32. pERK expression is elevated in RPIA transgenic fish aged 7 to 11 months.    114
Figure 33. The expression of β-catenin and downstream target genes were enhanced in rpia transgenic fish aged 7 to 11 months.    116
Figure 34. Knock down of RPIA in hepatoma cell lines results in a reduction of β-catenin protein expression.    118
Figure 35. RPIA transgenic zebrafish develops steatosis, hyperplasia, dysplasia, and HCC at earlier stages than control zebrafish.    120
Appendixes    121
Appendix 1. RPIA is positive correlated with β-catenin in lung.    121
Appendix 2. RPIA and β-catenin have similar expression pattern in prostate and thyroid.    123
Appendix 3. RPIA has a negative correlation with β-catenin in pancreas tissue.    124
Appendix 4. β-Catenin expression levels are opposite of RPIA in cervix uteri and kidney tissue.    126
Appendix 5. Up-regulation of RPIA and down-regulation of β-catenin are observed in uterine.    127
Appendix 6. RPIA is up-regulated in Testis tissue.    128
Appendix 7. β-Catenin is up-regulated in Skin nucleus.    129
Appendix 8. RPIA is down-regulated in Brain nucleus.    130
Appendix 9. β-Catenin is down-regulated in head and neck and soft tissue.    132
Appendix 10. RPIA and β-catenin have no significant difference between normal and tumor tissues in esophagus and stomach.    134
Appendix 11. RPIA and β-catenin have no significant difference between normal and tumor tissues in breast and ovary.    136
Appendix 12. RPIA and β-catenin have no significant difference between normal and tumor tissues in bladder and lymph node.    138
Tables    139
Table 1. Summary of RPIA and β-catenin expression patterns in different tumor biopsy compared with normal    139
Table 2. The primer information for qPCR analysis in human cancer cells    140
Table 3. The primer information for qPCR analysis in RPIA transgenic zebrafish    141
References    142
Publications    162
International Symposium Presentations    163
Honors & Awards    164

                                

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