博碩士論文 992404002 詳細資訊




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姓名 吳俊誼(Jun-I Wu)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 Crabp2 透過 HuR 以及 Integrin β1/FAK/ERK 訊 息傳導促進肺癌細胞轉移
(Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling)
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摘要(中) 許多類型的癌症腫瘤已經發現會高表現 CRABP2 並且關聯到病人的較差存活率。肺癌腫瘤也已經發現會高表現 CRABP2 ,但是 CRABP2 在肺癌轉移中的角色仍不清楚。本研究發現 Crabp2 在高轉移能力的 C10F4 肺癌細胞的表現會高過低轉移能力的肺癌細胞。我們發現 CRABP2 在臨床檢體的高表現與淋巴轉移,較差的存活率以及較高的復發率有關。抑制 Crabp2 的表現量會降低肺癌細胞的移動,侵襲,懸浮狀態下的存活率,以及老鼠模式中的轉移能力。 在免疫沉澱法中, Crabp2 能夠與 HuR 共同沉澱。 高表現 Crabp2 可以增加 HuR 的表現量,並且HuR可以促進 integrin β1 表現以及 FAK 和 ERK 的磷酸化。 抑制 HuR 或是 integrin β1 的表現,亦或是對細胞處理 FAK 或 ERK 的抑制劑都能夠降低 Crabp2 促進肺癌細胞移動,侵襲,以及懸浮狀態下存活率的能力。 另外,與單獨處理 gemcitbine 或是 irinotecan 相比,抑制 Crabp2 能夠進一步抑制肺癌細胞的生長。 CRABP2 在人類腫瘤檢體中的表現量與細胞壓力 (stress) 標記分子 CHOP 的表現量呈現正相關。 因此,我們的研究顯示出 Crabp2 在肺癌細胞轉移中扮演促進的角色。 CRABP2 可以作為一個潛在的預後標記分子,並且標靶 CRABP2 可以作為一個潛在的抑制肺癌轉移策略。 此外,我們也發現了間隙蛋白 Connexin 30.3 (Cx30.3, GJB4) 會促進肺癌細胞的轉移能力,因此我們也回顧了連接蛋白 (gap junction proteins, connexins)在癌症轉移中的角色。 間隙蛋白是一種四次穿膜的蛋白,能夠在相鄰的兩個細胞中間形成間隙連接 (gap junction) 並且因此促進細胞間的溝通 (gap junctional intercellular communication; GJIC) 。 傳統上認為間隙蛋白的角色在於形成半通道 (hemichannels) 後進一步組裝成間隙連接,並以此促進離子以及小分子的傳遞。 許多研究中均觀察到原位腫瘤細胞中的間隙蛋白表現量下降或是移位到細胞質內,因而造成 GJIC 的缺失。 因此,間隙蛋白一般被認為會抑制腫瘤。 然而,近年的研究發現了間隙蛋白在癌症轉移中可能還扮演不同的角色: 在病人的轉移組織切片中發現了 Connexin 43 (Cx43, GJA1) 以及 Connexin 26 (Cx26, GJB2) 的表現量以及它們出現在細胞膜的比率相較於原位腫瘤有所上升。 Cx43 以及 Cx26 所調控的 GJIC 能夠促進癌細胞的移動能力以及對於胸腔內皮細胞的貼附。 許多研究也報導了間隙蛋白在不同癌症類型中的表現以及功能。 在這裡我們聚焦回顧並且討論 1) 間隙蛋白在臨床檢體上的表現與病人預後的關聯性,2) 間隙蛋白在癌症轉移以及抗藥性中的角色,以及3) 將標靶間隙蛋白的分子作為抑制轉移藥物的應用以及考量。 總結來說,間隙蛋白可以做為潛在的癌症預後標記分子,以及開發干擾癌症轉移以及抗藥性的標的。
摘要(英) Increased CRABP2 levels have been found in various types of cancer, and are associated with poor patients’ survival. Although CRABP2 is found to be overexpressed in lung cancer, its role in metastasis of lung cancer is unclear. In this study, Crabp2 was overexpressed in high-metastatic C10F4 than low-metastatic lung cancer cells. Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. Crabp2 was co-immunoprecipitated with HuR, and overexpression of Crabp2 increased HuR levels, which promoted integrin β1/FAK/ERK signaling. Inhibition of HuR or integrin β1/FAK/ERK signaling reversed the promoting effect of Crabp2 in migration, invasion, and anoikis resistance. Knockdown of Crabp2 further inhibited the growth of cancer cells as compared with that by gemcitabine or irinotecan alone. The expression of Crabp2 in human lung tumors was correlated with stress marker CHOP. In conclusion, our findings have identified the promoting role of Crabp2 in anoikis resistance and metastasis. CRABP2 may serve as a prognostic marker and targeting CRABP2 may be exploited as a modality to reduce metastasis. In parallel, our laboratory has found the promoting role of Connexin 30.3 (Cx30.3, GJB4) in metastasis of lung cancer cells, and thus we reviewed the role of gap junction protein connexins in cancer metastasis. Connexin, a four-pass transmembrane protein, contributes to the assembly of gap junctions among neighboring cells and thus facilitates gap junctional intercellular communication (GJIC). Traditionally, the roles of connexins were thought to mediate formation of hemichannels and GJIC assembly for transportation of ions and small molecules. Many studies have observed loss of GJIC, due to reduced expression or altered cytoplasmic localization of connexins, in primary tumor cells. Connexins are generally considered tumor-suppressive. However, recent studies of clinical samples suggested a different role of connexins in that expression levels and membrane localization of connexins, including Connexin 43 (Cx43, GJA1) and Connexin 26 (Cx26, GJB2), were found to be enhanced in metastatic lesions of cancer patients. Cx43- and Cx26-mediated GJIC was found to promote cancer cell migration and adhesion to the pulmonary endothelium. Regulatory circuits involved in the induction of connexins and their functional effects have also been reported in various types of cancer. Here we focus on the recent findings in the correlation between the expression of connexins and patients’ prognosis, their roles in metastasis and chemoresistance, as well as the implications and concerns of using connexin-targeting drugs as anti-metastatic therapeutics. Overall, connexins may serve as biomarkers for cancer prognosis and as therapeutic targets for intervening metastasis and chemoresistance.
關鍵字(中) ★ 肺癌
★ 轉移
★ Crabp2
★ HuR
關鍵字(英) ★ Lung cancer
★ Metastasis
★ Crabp2
★ HuR
論文目次 中文摘要 I
Abstract III
Declaration V
Acknowledgments VI
Publications arising from this thesis VII
Table of contents VIII
Abbreviation XII
Chapter I: Introduction 1
Epidemiology of lung cancer 1
Cancer metastasis 1
The role of Crabp2 in cancer progression 2
The role of HuR in cancer progression 2
The role of gap junction proteins connexins in cancer progression 3
Figures 6
Figure I-1. The assembly of connexins into gap junctions. 6
Chapter II: Materials and Methods 7
Cell culture 7
Establishment of high-metastatic subline 7
RNA extraction and real-time RT-PCR 7
Tissue Samples 8
Exon array 8
Antibodies and reagents 8
Western blot 9
Migration and invasion assay 9
Generation of stable cell lines and plasmid construction 9
Anoikis assay 10
Tail vein metastasis assay 10
IHC staining and analysis 11
Cell viability assays 11
Immunoprecipitation 11
Statistical analysis 11
Table 13
Table II-1. The list of primers and oligomers used in this study. 13
Table II-2. Information on antibodies and reagents used in this study. 16
Chapter III: Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling 18
Rationale 18
Results 18
Establishment of high-metastatic C10F4 lung cancer cells 18
Crabp2 is overexpressed in high-metastatic C10F4 lung cancer cells 19
CRABP2 is associated with tumor progression, poor overall survival, and recurrence of lung cancer patients 20
Knockdown of Crabp2/CRABP2 suppresses migration, invasion, anoikis resistance, and in vivo metastasis 21
Crabp2 promotes integrin β1/FAK/ERK signaling via HuR 22
Crabp2 promotes migration, invasion, and anoikis resistance via HuR and integrin β1/FAK/ERK signaling 23
CRABP2/Crabp2 knockdown has an additive but not synergistic effect on the inhibitory effects of gemcitabine and irinotecan on cell viability 24
Identification of the upstream regulating factor(s) of Crabp2 25
Discussion 26
Figures 29
Figure III-1. C10F4 cells have higher migration and invasion ability than C9F6 cells. 29
Figure III-2. C10F4 cells have higher metastasis ability than C9F6 cells. 30
Figure III-3. Time course of lung metastasis of C10F4 and C9F6 cells. 31
Figure III-4. Crabp2 is overexpressed in C10F4 than C9F6 cells and CRABP2 is a lung tumor-overexpressing gene. 32
Figure III-5. CRABP2 is a lung tumor-overexpressing gene. 34
Figure III-6. Crabp2 is overexpressed in C10F4 cells. 35
Figure III-7. CRABP2 is overexpressed in blood buffy coat RNA samples of N2-N3 patients. 36
Figure III-8. CRABP2 is associated with advanced tumor stage and lymph node status of lung cancer patients. 37
Figure III-9. CRABP2 is associated with poor overall survival of lung cancer patients. 38
Figure III-10. CRABP2 is associated with poor survival of lung cancer patients. 39
Figure III-11. CRABP2 is associated with first progression after surgery of lung cancer patients. 40
Figure III-12. CRABP2 is associated with recurrence of lung cancer patients. 41
Figure III-13. Knockdown of Crabp2/CRABP2. 42
Figure III-14. Knockdown of Crabp2 inhibited proliferation of C10F4 cells. 43
Figure III-15. Knockdown of Crabp2 inhibited migration and invasion of C10F4 cells. 44
Figure III-16. Knockdown of CRABP2 inhibited migration and invasion of H1650 cells. 45
Figure III-17. Knockdown of Crabp2 inhibited anoikis resistance of C10F4 cells. 46
Figure III-18. Knockdown of CRABP2 inhibited anoikis resistance of H1650 cells. 47
Figure III-19. Knockdown of Crabp2 inhibited metastasis of C10F4 cells. 48
Figure III-20. The inhibitory effect of retinoic acid on anoikis resistance of C10F4 cells is irrelative to Crabp2. 49
Figure III-21. Crabp2 is co-immunoprecipitated with HuR. 50
Figure III-22. HuR and ITGB1 are inhibited by knockdown of Crabp2 in C10F4 cells. 51
Figure III-23. HuR and ITGB1 are enhanced by overexpression of Crabp2 in C10F4 cells. 52
Figure III-24. Knockdown of Crabp2/CRABP2 inhibits HuR-ITGB1/FAK/ERK signaling. 53
Figure III-25. Overexpression of Crabp2/CRABP2 promotes HuR-ITGB1/FAK/ERK signaling. 54
Figure III-26. Knockdown of HuR and ITGB1 by siRNAs. 55
Figure III-27. HuR and ITGB1/FAK/ERK signaling are needed by Crabp2 to promote the migration and invasion of C10F4 cells. 56
Figure III-28. HuR is needed by Crabp2 to promote the anoikis resistance of C10F4 cells. 57
Figure III-29. ITGB1/FAK/ERK signaling is needed by Crabp2 to promote the anoikis resistance of C10F4 cells. 58
Figure III-30. C10F4 cells are not sensitive to erlotinib. 59
Figure III-31. H1650 cells are not sensitive to erlotinib. 60
Figure III-32. CRABP2 knockdown has an additive but not synergistic effect on the inhibitory effects of gemcitabine and irinotecan on H1650 cell viability. 61
Figure III-33. Crabp2 knockdown further inhibited the growth of C10F4 cells as compared with that by gemcitabine or irinotecan alone. 62
Figure III-34. Crabp2 is inducible by tunicamycin. 63
Figure III-35. CRABP2, CHOP, E2F1, E2F7 are overexpressed in lung tumors. 64
Figure III-36. High CHOP levels are associated with poor survival and first progression after surgery of lung cancer patients. 65
Figure III-37. CRABP2 is correlated with CHOP in human lung tumors. 66
Figure III-38. CRABP2 is correlated with cell stress marker CHOP, E2F1, and E2F7. 67
Figure III-39. Working hypothesis of this study. 68
Tables 69
Table III-1. Correlation of CRABP2 expression levels with clinicopathologic features of lung tumors. 69
Table III-2. Multivariate survival analysis of CRABP2 in lung cancer. 71
Table III-3. Multivariate survival analysis of ERCC1 in lung cancer. 72
Table III-4. Multivariate survival analysis of p27 in lung cancer. 73
Table III-5. Multivariate survival analysis of RRM1 in lung cancer. 74
Table III-6. CRABP2 mRNA levels in sensitive and resistant lines of seven chemotherapeutics using data from Barrentina. 75
Chapter IV: (Review) Emerging Roles of Gap Junction Proteins Connexins in Cancer Metastasis, Chemoresistance and Clinical Application 77
Rationale 77
Connexin 43: 77
The suppressing roles Connexin 43 in tumorigenesis 77
Increased expression and membrane localization of Connexin 43 in metastatic lesions 79
Connexin 43-mediated GJIC enhances cell-cell adhesion and extravasation 79
Carboxyl-terminal tail of Connexin 43 promotes cell migration via p38 81
MicroRNAs that regulate metastatic behaviors of cancer cells via targeting Connexin 43 82
The transcriptional regulation for Connexin 43 expression 83
Connexin 26: 84
Cytoplasmic Connexin 26 is correlated with lymph node metastasis and poor prognosis 84
Cytoplasmic Connexin 26 promotes tumor growth, EMT, and invasion 84
Increased expression and membrane localization of Connexin 26 in metastatic lesions 85
Connexin 26-mediated GJIC promotes migration as single cells via reducing cell-cell adhesion 85
Connexin 32: 87
Cytoplasmic Connexin 32 promotes proliferation, migration and metastasis 87
Connexin 32-mediated GJIC inhibits migration via enhancing cell-cell aggregation 87
Connexin 31, 31.1, 46, and 30.3: 88
Connexins in tumor stroma: 89
Increased Connexin 43, 26, and 30 levels in tumor stroma 89
Stromal Cx43 promotes migration and invasion via GJIC 90
Effects of connexins on chemotherapy 90
Bystander effects mediated by GJIC 90
The GJIC-independent role of connexins in chemotherapy 91
Factors contributing to the variety of connexin-mediated functions 92
Therapeutic applications of connexins as targets 94
Compounds against connexins as potential anti-metastatic drugs 94
Connexins involved in the anti-metastatic effects of therapeutics 95
Figures 97
Figure IV-1. Functional roles of Cx43 in tumor progression. 97
Figure IV-2. Regulatory circuits of Cx43 in tumor progression. 98
Figure IV-3. Functional roles of Cx26 and Cx32 in tumor progression. 99
Tables 100
Table IV-1. Cx43 expression in clinical samples and its correlation with patients’ clinical outcomes. 100
Table IV-2. Cx26/Cx32 expression in clinical samples and their correlation with patients’ clinical outcomes. 102
Table IV-3. Novel compounds that target connexins to inhibit metastasis. 104
Chapter V: General discussion and future works 106
CRABP2 is a potential blood marker assessing lymph node status of lung cancer patients 106
Genes promoting metastasis could be different from those for primary tumor growth 107
The potential link between the Crabp2-HuR axis and connexins/other proteins regulating metastatic behaviors of lung cancer cells 107
Concerns of targeting connexins and potential strategies 108
To develop the peptide inhibitor for the Crabp2-HuR interaction 109
To validate if Crabp2 regulates Cx32 levels via HuR 110
To validate if the Crabp2 levels of white blood cells can be affected by lung tumor cells 110
To validate if Crabp2 regulates stem cell-like features of lung cancer cells 111
To validate if blood CRABP2 levels are enhanced in early stage lung cancer patients versus healthy people and can serve as an early detection marker for lung cancer 111
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指導教授 王陸海 陳盛良(Lu-Hai Wang Shen-Liang Chen) 審核日期 2019-3-29
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