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研究生：	林原禾 Lin, Yuan-Ho
論文名稱：	抑制長鏈非編碼核糖核酸RPPH1的活性能下調發炎相關的致癌基因以減少腫瘤的生長與轉移 Inhibition of lncRNA RPPH1 activity decreases tumor proliferation and metastasis through down-regulation of inflammation-related oncogenes
指導教授：	張文粲 Chang, Wen-Tsan
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	103
中文關鍵詞：	長鏈非編碼核糖核酸、RPPH1 、轉運核糖核酸、癌症、發炎、白细胞介素6
外文關鍵詞：	LncRNA, RPPH1, tRNA, HeLa, MDA-MB-231, inflammation, cancer, IL-6
相關次數：	點閱：83 下載：0
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核糖核酸酶 P是由十個相異的蛋白單元以及一個核糖核酸所組成的酵素，在細胞中負責切割 tRNA 5’端並使其轉變為成熟的tRNA。早期的研究中發現，過度表現核糖核酸酶 P中的核醣核酸單元-RPPH1會促進癌細胞的生長與發展，然而其詳細機制仍尚未明瞭。為了調查RPPH1在腫瘤發展中所扮演的角色，我們設計出能高專一性與RPPH1結合的shRNA以作為研究手段。藉由次世代定序與生物資訊的方式分析RPPH1抑制細胞(HeLa與MDA-MB-231)與控制組細胞後一共列出40個顯著被下調節的基因。這些被下調的基因主要參與tRNA路徑、免疫反應與癌症相關發炎反應(IL-6路徑)。為了證實生物資訊分析的結果，我們分析了RPPH1抑制細胞與控制組細胞的生長與轉移。實驗的結果呈現出RPPH1抑制細胞比起控制組細胞其生長與轉移能力均顯著的降低。我們證明了抑制RPPH1後所導致的G1細胞週期延遲主要是透過下調細胞週期蛋白D1所導致。此外，RPPH1抑制細胞內的糖解酵素(HK1與HK2)也會被下調。總結來說，這些結果證實抑制RPPH1能下調發炎相關的致癌基因並減少腫瘤的發展。這項研究為RPPH1在腫瘤的發展中所扮演的角色提供了新的觀點。

Ribonuclease P RNA component H1 (RPPH1) is an RNA subunit of RNase P that plays a central role in RNase P-mediated pre-tRNA cleavage. Previous studies showed that overexpression of RPPH1 promotes tumor growth and progression, but the molecular mechanism is still unclear. To investigate the role and function of RPPH1 in cancer malignancy, short hairpin RNAs were designed to specifically target RPPH1. A total of 40 significantly down-regulated genes between RPPH1 knockdown (HeLa-shRPPH1-1-52 and MDA-MB-231-shRPPH1-1-72) and mock cells were identified using next-generation sequencing and bioinformatics analysis. The results indicate that these down-regulated genes are the major genes involved in tRNA pathways, immune response, and cancer-related inflammation (IL-6 pathway). To confirm the results of the bioinformatics analysis, RPPH1-silenced cells were analyzed using various experiments. A significant down-regulation of tumor proliferation and migration was observed in RPPH1 knockdown cells compared to that of mock- and vector-transfected cells. We demonstrate that the inhibition of RPPH1 promotes cell cycle arrest in the G1 phase mainly through the down-regulation of cyclin D1. In addition, the glycolytic enzyme (HK1 and HK2) is also down-regulated in RPPH1-silenced HeLa cells. Taken together, these results clearly reveal that the knockdown of RPPH1 expression decreases tumor progression via the down-regulation of inflammation-related oncogene. This study provides insight into the role of RPPH1 in tumor development.

一、中文摘要	I
二、Abstract	II
三、誌謝	III
四、Table of Contents	IV~VIII
五、Main text
 Chapter 1. Introduction	1~8
  1.1 Inflammation and Cancer	2
  1.2 Hallmarks of cancer	3
  1.3 Reprogramming of energy metabolism	4
  1.4 Translational alteration in cancer	5
  1.5 Ribonuclease P	5~6
  1.6 Metabolic reprogramming of SDH-deficient cancers	6~7
  1.7 Study aim	7~8

Chapter 2. Materials and Methods	9~18
  Materials	10~13
  Methods	14~18
  2.1 Cell culture	14
  2.2 Cell transfection	14
  2.3 Design and construction of the shRNA expression vector	14~15
  2.4 Next-Generation Sequencing	15
  2.5 MTT cell growth assay	15
  2.6 Colony formation assay	16
  2.7 Wound healing migration assay	16
  2.8 Boyden chamber migration assay	16
  2.9 Cell synchronization by double thymidine block	17
  2.10 Western blot analysis	17
  2.11 pH measurement in conditioned medium	18
  2.12 Immunohistochemical staining	18

 Chapter 3. Results	19~27
  Project 1
  3.1 RPPH1 expression in various cancers and affect on prognosis	20
  3.2 Construction and identification of differentially expressed genes in RPPH1 knockdown cancer cells	20~21
  3.3 Top 40 potential down-regulated genes in RPPH1 knockdown cells	21
  3.4 Inhibition of RPPH1 expression decreases mature tRNA generation and several tRNA pathways	21~22
  3.5 Down-regulation of RPPH1 expression decreases tumor cell proliferation and migration	22~23
  3.6 RPPH1 knockdown cells promote G1 arrest through down-regulation of cyclin D1	23~24
  3.7 Down-regulated RPPH1 affects glycolytic pathway in cervical cancer	24
  Project 2
  3.8 High SDHC expression in various cancers as compared to SDHB subunits     	25
  3.9 SDHC overexpression correlates with poor prognosis in lung cancers        	25~26
  3.10 Inhibition of SDHC decreases lung cancer cell proliferation and migration    	26~27
  3.11 Inhibition of SDHC expression promotes the up-regulation of SDHA protein expression	27

Chapter 4. Discussion	28~34
  Project 1
  4.1 The role of RPPH1 in tumor protein synthesis	29
  4.2 Link between RPPH1 and cancer-related inflammation	30
  4.3 The role of RPPH1 in the glycolytic pathway	31
  4.4 Inhibition of RPPH1 affects the function of RNase P	31~32
  4.5 Conclusion	32
  Project 2
  4.6 High SDHC expression is associated with the malignancy of lung cancer cells and poor prognosis	32~33
  4.7 Up-regulation of SDHA reduces the accumulation of succinate	33
  4.8 Conclusion	34

Chapter 5. References	35~45

六、Table and Figures	46~74
  Table	47
  Table 1. Enrichment by pathways maps	47

  Figures	48~74
  Project 1
  Figure 1. High RPPH1 expression in various human cancers	48
  Figure 2. Tumors with high RPPH1 expression exhibit a poor prognosis	49
  Figure 3. Flowchart of study design	50
  Figure 4. Differentially expressed RNA between RPPH1 knockdown cells and mock cells	51
  Figure 5. Potential pathways of down-regulated gene in RPPH1 silencing cells	52
  Figure 6. Top 40 potential down-regulated genes in RPPH1 knockdown cells	53
  Figure 7. Several amino acid pathways and tRNA production were down-regulated in RPPH1 inhibited cells	54
  Figure 8. RPPH1 inhibited cells decrease IL-6 protein expression	55
  Figure 9. Inhibition of RPPH1 decreases cancer cell proliferation and migration...56~57
  Figure 10. Knockdown of RPPH1 decreases cell cycle progression	58
  Figure 11. RPPH1 inhibited HeLa cell down-regulates the expression of glucose pathway-related genes	59
  Figure 12. RPPH1 inhibited cells decrease glucose dependence and uptake	60
  Figure 13. Potential pathway of RPPH1 in cervical cancer	61
  Project 2
  Figure 14. Gene expression of SDH subunits in various tumors	62
  Figure 15. SDHC expression is related to the lung cancer malignancy	63
  Figure 16. Lung cancers with high SDHC expression exhibit a poor prognosis	64
  Figure 17. Construction of SDHC knockdown A549 and H1299 cells	65
  Figure 18. Knockdown of SDHC decreases cancer cell proliferation and colony formation	66
  Figure 19. Inhibition of SDHC decreases tumor migration	67
  Figure 20. Knockdown of SDHC decreases mobility of lung cancer cells 	68
  Figure 21. Inhibition of SDHC increases SDHA protein expression	69
  Supplemental Figures	70~74
  Figure S1. Tumors with high Rpp40 expression exhibit a poor prognosis	70
  Figure S2. Inhibition of Rpp40 decreases cancer cell proliferation and migration	…..71~72
  Figure S3. Inhibition of Rpp40 decreases cell cycle progression	73
  Figure S4. Rpp40 inhibited cells decrease glucose dependence and uptake	74
六、Publication List	75~103

                                    

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