跳到主要內容

臺灣博碩士論文加值系統

(100.28.2.72) 您好!臺灣時間:2024/06/13 12:25
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:Shubham Suresh Ghule
論文名稱(外文):An Investigation Role of the Ugonin P in Human lung cancer
指導教授:湯智昕
指導教授(外文):TANG, CHIH-HSIN
口試委員:黃偉謙廖志中簡銘賢
口試委員(外文):HUANG, WEI-CHIENLIAW, CHIH-CHUANGCHIEN, MING-HSIEN
口試日期:2023-06-19
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:國際生物醫學碩士學位學程
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:2023
畢業學年度:111
語文別:英文
論文頁數:52
外文關鍵詞:Lung cancerMigrationInvasionUgonin PDPP-4miR-130b 5p
相關次數:
  • 被引用被引用:0
  • 點閱點閱:55
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
Abstract
Extracts from the Helminthostatchys zeylanica (H. zeylanica) are a renowned Chinese herbal medicine and thus exhibit anti-inflammatory, immunomodulatory, and anticancer activities in various cellular and animal studies. Recently it has been identified that H. zeylanica exhibits anticancer activity in gastric cancer and liver cancer. However, the role of H. zeylanica derivatives in lung cancer remains unclear. Dipeptidyl peptidase-4 (DPP-4) is a sugar-coated protein and is widely present on the exterior of different types of cells. Regulation of DPP-4 is disturbed in various diseases such as cancer. DPP-4 expression varies in primary tumors depending on tumor type, stage, and microenvironment and may regulate cancer behavior. For the first time, our study has identified that H. Zeylanica derivative Ugonin P attenuates lung cancer cell motility and invasion by targeting DPP-4. Our results revealed that the level of DPP-4 expression was high in human lung tissue array specimens and clinical samples of bioinformatic analysis with the lung cancer and healthy specimens. Ugonin P dose-dependently inhibited DPP-4 mRNA and protein expressions in both cell lines detected by qPCR and western blot assay. In addition, Ugonin P diminished migration and invasion in both cell lines investigated by the Transwell migration chamber. These effects appeared to be mediated by DPP-4 via RAF/MEK/ERK signaling. miRNAs are short noncoding double-stranded RNA molecules. miRNA is known for regulating protein functions, our miRNA sequencing shows that miR-130b-5p is highly upregulated in Ugonin P treated cells. miR-130b-5p negatively regulates DPP-4 protein expression in lung cancer. Our investigation demonstrates that Ugonin P suppresses DPP-4 expression and lung cancer cell migration and invasion via RAF/MEK/ERK and by upregulating miR-130b-5p.

CONTENTS
ABSTRACT I
CONTENTS II
LIST OF FIGURES V
LIST OF TABLES VI
LIST OF APPENDIX FIGURES VI
ABBREVIATIONS VII
CHAPTER 1. INTRODUCTION 1
1.1. LUNG CANCER 1
1.1.1. Non-Small Cell Lung Cancer 1
1.1.1.1 Adenocarcinoma 1
1.1.1.2 Squamous Cell Carcinoma 1
1.1.1.3 Large Cell Carcinoma 1
1.2. EPIDEMIOLOGY 2
1.3. DIAGNOSIS AND TREATMENT 2
1.4. STAGES OF NON-SMALL CELL LUNG CANCER 4
1.5. LUNG CANCER METASTASIS 5
1.5.1 The development and movement of cancer cells 5
1.5.2 Invasion of blood vessels 6
1.5.3 Extravasation 6
1.5.4 Developing a remote metastatic site 6
1.6. DIPEPTIDYL PEPTIDASE 4 7
1.7. HELMINTHOSTACHYS ZEYLANICA (UGONIN P) 7
1.8. MICRO RNAS 8
1.9. RESEARCH AIM 9
CHAPTER 2. MATERIALS AND METHODS 10
2.1. MATERIALS 10
2.2. EXPERIMENTAL METHODS 15
2.2.1 Cell Culture 15
2.2.2 Cell viability assay 16
2.2.3 Quantitative Real-Time PCR 16
2.2.4 Western blot 17
2.2.5 Migration Assay 18
2.2.6 Invasion Assay 18
2.2.7 Gene expression omnibus Database (GEO Database) 19
2.2.8 Transfection 19
2.2.9 Immunohistochemistry (IHC) 20
2.2.10 Protein Array 20
2.2.11 Statistical Analysis 21
CHAPTER 3. RESULTS 22
3.1. UGONIN P DOESN’T ALTER THE LUNG CANCER CELL VIABILITY 22
3.2. UGONIN P SUPPRESS THE NON-SMALL CELL LUNG CANCER MIGRATION AND INVASION 22
3.3. DPP-4 IS TARGETED AND DOWNREGULATED BY UGONIN P INVOLVED IN LUNG CANCER 22
3.4. LEVEL OF DPP-4 EXPRESSION DETERMINED FROM DATABASES AND HUMAN LUNG CANCER TISSUE ARRAY 23
3.5. DPP-4 PROMOTES LUNG CANCER CELL MIGRATION AND INVASION SUPPRESS BY UGONIN P 23
3.6. RAF/MEK/ERK PATHWAY IS INOVOLVED IN UGONIN P INHIBITION NSCLC MIGRATION AND INVASION AS WELL AS DPP-4 EXPRESSION 24
3.7. MIR-130B-5P REGULATES DPP-4, UPREGULATED BY UGONIN P 25
3.8. MODULATION OF MIR-130B-5P INTERCEDES THE ABILITY OF UGONIN P TO SUPPRESS DPP-4 AND HUMAN LUNG CANCER CELL MIGRATION AND INVASION 26
CHAPTER 4. DISCUSSION 27
CHAPTER 5. CONCLUSION 30
CHAPTER 6. RESULT FIGURES 31
CHAPTER 7. GRAPHICAL ABSTRACT 39
CHAPTER 8. APPENDIX 40
CHAPTER 9. REFERENCES 45


REFERENCES
1.Oliver, A.L. Lung Cancer: Epidemiology and Screening. Surg Clin North Am 2022, 102, 335-344, doi:10.1016/j.suc.2021.12.001.
2.Flores, E.J.; Park, E.R.; Irwin, K.E. Improving Lung Cancer Screening Access for Individuals With Serious Mental Illness. J Am Coll Radiol 2019, 16, 596-600, doi:10.1016/j.jacr.2018.12.045.
3.Rodriguez-Canales, J.; Parra-Cuentas, E.; Wistuba, II. Diagnosis and Molecular Classification of Lung Cancer. Cancer Treat Res 2016, 170, 25-46, doi:10.1007/978-3-319-40389-2_2.
4.Nooreldeen, R.; Bach, H. Current and Future Development in Lung Cancer Diagnosis. Int J Mol Sci 2021, 22, doi:10.3390/ijms22168661.
5.Zheng, M. Classification and Pathology of Lung Cancer. Surg Oncol Clin N Am 2016, 25, 447-468, doi:10.1016/j.soc.2016.02.003.
6.Hutchinson, B.D.; Shroff, G.S.; Truong, M.T.; Ko, J.P. Spectrum of Lung Adenocarcinoma. Semin Ultrasound CT MR 2019, 40, 255-264, doi:10.1053/j.sult.2018.11.009.
7.Lau, S.C.M.; Pan, Y.; Velcheti, V.; Wong, K.K. Squamous cell lung cancer: Current landscape and future therapeutic options. Cancer Cell 2022, 40, 1279-1293, doi:10.1016/j.ccell.2022.09.018.
8.Weissferdt, A. Large cell carcinoma of lung: On the verge of extinction? Semin Diagn Pathol 2014, 31, 278-288, doi:10.1053/j.semdp.2014.06.005.
9.Duma, N.; Santana-Davila, R.; Molina, J.R. Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment. Mayo Clin Proc 2019, 94, 1623-1640, doi:10.1016/j.mayocp.2019.01.013.
10.Gridelli, C.; Rossi, A.; Carbone, D.P.; Guarize, J.; Karachaliou, N.; Mok, T.; Petrella, F.; Spaggiari, L.; Rosell, R. Non-small-cell lung cancer. Nat Rev Dis Primers 2015, 1, 15009, doi:10.1038/nrdp.2015.9.
11.Nasim, F.; Sabath, B.F.; Eapen, G.A. Lung Cancer. Med Clin North Am 2019, 103, 463-473, doi:10.1016/j.mcna.2018.12.006.
12.Postmus, P.E.; Kerr, K.M.; Oudkerk, M.; Senan, S.; Waller, D.A.; Vansteenkiste, J.; Escriu, C.; Peters, S.; Committee, E.G. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017, 28, iv1-iv21, doi:10.1093/annonc/mdx222.
13.Thakur, S.K.; Singh, D.P.; Choudhary, J. Lung cancer identification: a review on detection and classification. Cancer Metastasis Rev 2020, 39, 989-998, doi:10.1007/s10555-020-09901-x.
14.Wang, M.; Herbst, R.S.; Boshoff, C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med 2021, 27, 1345-1356, doi:10.1038/s41591-021-01450-2.
15.Alexander, M.; Kim, S.Y.; Cheng, H. Update 2020: Management of Non-Small Cell Lung Cancer. Lung 2020, 198, 897-907, doi:10.1007/s00408-020-00407-5.
16.O'Sullivan, B.; Brierley, J.; Byrd, D.; Bosman, F.; Kehoe, S.; Kossary, C.; Pineros, M.; Van Eycken, E.; Weir, H.K.; Gospodarowicz, M. The TNM classification of malignant tumours-towards common understanding and reasonable expectations. Lancet Oncol 2017, 18, 849-851, doi:10.1016/S1470-2045(17)30438-2.
17.Maghfoor, I.; Perry, M.C. Lung cancer. Ann Saudi Med 2005, 25, 1-12, doi:10.5144/0256-4947.2005.1.
18.Fares, J.; Fares, M.Y.; Khachfe, H.H.; Salhab, H.A.; Fares, Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther 2020, 5, 28, doi:10.1038/s41392-020-0134-x.
19.Seyfried, T.N.; Huysentruyt, L.C. On the origin of cancer metastasis. Crit Rev Oncog 2013, 18, 43-73, doi:10.1615/critrevoncog.v18.i1-2.40.
20.Popper, H.H. Progression and metastasis of lung cancer. Cancer Metastasis Rev 2016, 35, 75-91, doi:10.1007/s10555-016-9618-0.
21.He, H.; Shao, X.; Li, Y.; Gihu, R.; Xie, H.; Zhou, J.; Yan, H. Targeting Signaling Pathway Networks in Several Malignant Tumors: Progresses and Challenges. Front Pharmacol 2021, 12, 675675, doi:10.3389/fphar.2021.675675.
22.Guo, Y.J.; Pan, W.W.; Liu, S.B.; Shen, Z.F.; Xu, Y.; Hu, L.L. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med 2020, 19, 1997-2007, doi:10.3892/etm.2020.8454.
23.Ullah, R.; Yin, Q.; Snell, A.H.; Wan, L. RAF-MEK-ERK pathway in cancer evolution and treatment. Semin Cancer Biol 2022, 85, 123-154, doi:10.1016/j.semcancer.2021.05.010.
24.Wen, Z.; Jiang, R.; Huang, Y.; Wen, Z.; Rui, D.; Liao, X.; Ling, Z. Inhibition of lung cancer cells and Ras/Raf/MEK/ERK signal transduction by ectonucleoside triphosphate phosphohydrolase-7 (ENTPD7). Respir Res 2019, 20, 194, doi:10.1186/s12931-019-1165-0.
25.Castaneda, M.; den Hollander, P.; Kuburich, N.A.; Rosen, J.M.; Mani, S.A. Mechanisms of cancer metastasis. Semin Cancer Biol 2022, 87, 17-31, doi:10.1016/j.semcancer.2022.10.006.
26.Massagué, J.; Obenauf, A.C. Metastatic colonization by circulating tumour cells. Nature 2016, 529, 298-306, doi:10.1038/nature17038.
27.Majidpoor, J.; Mortezaee, K. Steps in metastasis: an updated review. Med Oncol 2021, 38, 3, doi:10.1007/s12032-020-01447-w.
28.Fife, C.M.; McCarroll, J.A.; Kavallaris, M. Movers and shakers: cell cytoskeleton in cancer metastasis. Br J Pharmacol 2014, 171, 5507-5523, doi:10.1111/bph.12704.
29.Zhu, T.; Bao, X.; Chen, M.; Lin, R.; Zhuyan, J.; Zhen, T.; Xing, K.; Zhou, W.; Zhu, S. Mechanisms and Future of Non-Small Cell Lung Cancer Metastasis. Front Oncol 2020, 10, 585284, doi:10.3389/fonc.2020.585284.
30.Röhrborn, D.; Wronkowitz, N.; Eckel, J. DPP4 in Diabetes. Front Immunol 2015, 6, 386, doi:10.3389/fimmu.2015.00386.
31.Mortier, A.; Gouwy, M.; Van Damme, J.; Proost, P.; Struyf, S. CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology. J Leukoc Biol 2016, 99, 955-969, doi:10.1189/jlb.3MR0915-401R.
32.Enz, N.; Vliegen, G.; De Meester, I.; Jungraithmayr, W. CD26/DPP4 - a potential biomarker and target for cancer therapy. Pharmacol Ther 2019, 198, 135-159, doi:10.1016/j.pharmthera.2019.02.015.
33.He, Q.; Cao, H.; Zhao, Y.; Chen, P.; Wang, N.; Li, W.; Cui, R.; Hou, P.; Zhang, X.; Ji, M. Dipeptidyl Peptidase-4 Stabilizes Integrin α4β1 Complex to Promote Thyroid Cancer Cell Metastasis by Activating Transforming Growth Factor-Beta Signaling Pathway. Thyroid 2022, 32, 1411-1422, doi:10.1089/thy.2022.0317.
34.Choi, H.J.; Kim, J.Y.; Lim, S.C.; Kim, G.; Yun, H.J.; Choi, H.S. Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression. Br J Pharmacol 2015, 172, 5096-5109, doi:10.1111/bph.13274.
35.Huang, Y.L.; Shen, C.C.; Shen, Y.C.; Chiou, W.F.; Chen, C.C. Anti-inflammatory and Antiosteoporosis Flavonoids from the Rhizomes of Helminthostachys zeylanica. J Nat Prod 2017, 80, 246-253, doi:10.1021/acs.jnatprod.5b01164.
36.Cao, L.; Li, R.; Chen, X.; Xue, Y.; Liu, D. Neougonin A Inhibits Lipopolysaccharide-Induced Inflammatory Responses via Downregulation of the NF-kB Signaling Pathway in RAW 264.7 Macrophages. Inflammation 2016, 39, 1939-1948, doi:10.1007/s10753-016-0429-9.
37.Tsai, M.M.; Lin, H.C.; Yu, M.C.; Lin, W.J.; Chu, M.Y.; Tsai, C.C.; Cheng, C.Y. Anticancer Effects of Helminthostachys zeylanica Ethyl acetate Extracts on Human Gastric Cancer Cells through Downregulation of the TNF-α-activated COX-2-cPLA2-PGE(2) Pathway. J Cancer 2021, 12, 7052-7068, doi:10.7150/jca.64638.
38.Subtelny, A.O.; Eichhorn, S.W.; Chen, G.R.; Sive, H.; Bartel, D.P. Poly(A)-tail profiling reveals an embryonic switch in translational control. Nature 2014, 508, 66-71, doi:10.1038/nature13007.
39.Le Quesne, J.; Caldas, C. Micro-RNAs and breast cancer. Mol Oncol 2010, 4, 230-241, doi:10.1016/j.molonc.2010.04.009.
40.Li, S.; Gao, M.; Li, Z.; Song, L.; Gao, X.; Han, J.; Wang, F.; Chen, Y.; Li, W.; Yang, J.; et al. Role of microRNAs in metastasis of non-small cell lung cancer. Front Biosci (Landmark Ed) 2016, 21, 998-1005, doi:10.2741/4436.
41.Yanaihara, N.; Caplen, N.; Bowman, E.; Seike, M.; Kumamoto, K.; Yi, M.; Stephens, R.M.; Okamoto, A.; Yokota, J.; Tanaka, T.; et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006, 9, 189-198, doi:10.1016/j.ccr.2006.01.025.
42.Chen, H.; Yang, Y.; Wang, J.; Shen, D.; Zhao, J.; Yu, Q. miR-130b-5p promotes proliferation, migration and invasion of gastric cancer cells via targeting RASAL1. Oncol Lett 2018, 15, 6361-6367, doi:10.3892/ol.2018.8174.
43.Wang, Y.; Han, J.; Lv, Y.; Zhang, G. miR-29a inhibits proliferation, invasion, and migration of papillary thyroid cancer by targeting DPP4. Onco Targets Ther 2019, 12, 4225-4233, doi:10.2147/ott.S201532.
44.Schabath, M.B.; Cote, M.L. Cancer Progress and Priorities: Lung Cancer. Cancer Epidemiol Biomarkers Prev 2019, 28, 1563-1579, doi:10.1158/1055-9965.Epi-19-0221.
45.Xie, S.; Wu, Z.; Qi, Y.; Wu, B.; Zhu, X. The metastasizing mechanisms of lung cancer: Recent advances and therapeutic challenges. Biomed Pharmacother 2021, 138, 111450, doi:10.1016/j.biopha.2021.111450.
46.Martínez-Ruiz, C.; Black, J.R.M.; Puttick, C.; Hill, M.S.; Demeulemeester, J.; Larose Cadieux, E.; Thol, K.; Jones, T.P.; Veeriah, S.; Naceur-Lombardelli, C.; et al. Genomic-transcriptomic evolution in lung cancer and metastasis. Nature 2023, 616, 543-552, doi:10.1038/s41586-023-05706-4.
47.Sears, C.R.; Mazzone, P.J. Biomarkers in Lung Cancer. Clin Chest Med 2020, 41, 115-127, doi:10.1016/j.ccm.2019.10.004.
48.Yamaguchi, T.; Watanabe, A.; Tanaka, M.; Shiota, M.; Osada-Oka, M.; Sano, S.; Yoshiyama, M.; Miura, K.; Kitajima, S.; Matsunaga, S.; et al. A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4. J Pharmacol Sci 2019, 139, 112-119, doi:10.1016/j.jphs.2018.12.004.
49.Stremenova, J.; Krepela, E.; Mares, V.; Trim, J.; Dbaly, V.; Marek, J.; Vanickova, Z.; Lisa, V.; Yea, C.; Sedo, A. Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade. Int J Oncol 2007, 31, 785-792.
50.Lemjabbar-Alaoui, H.; Hassan, O.U.; Yang, Y.W.; Buchanan, P. Lung cancer: Biology and treatment options. Biochim Biophys Acta 2015, 1856, 189-210, doi:10.1016/j.bbcan.2015.08.002.
51.Stokes, W.A.; Bronsert, M.R.; Meguid, R.A.; Blum, M.G.; Jones, B.L.; Koshy, M.; Sher, D.J.; Louie, A.V.; Palma, D.A.; Senan, S.; et al. Post-Treatment Mortality After Surgery and Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer. J Clin Oncol 2018, 36, 642-651, doi:10.1200/jco.2017.75.6536.
52.Patel, J.D.; Socinski, M.A.; Garon, E.B.; Reynolds, C.H.; Spigel, D.R.; Olsen, M.R.; Hermann, R.C.; Jotte, R.M.; Beck, T.; Richards, D.A.; et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 2013, 31, 4349-4357, doi:10.1200/jco.2012.47.9626.
53.Sever, R.; Brugge, J.S. Signal transduction in cancer. Cold Spring Harb Perspect Med 2015, 5, doi:10.1101/cshperspect.a006098.
54.Juliano, R.L. Addressing cancer signal transduction pathways with antisense and siRNA oligonucleotides. NAR Cancer 2020, 2, zcaa025, doi:10.1093/narcan/zcaa025.
55.Wani, J.A.; Majid, S.; Imtiyaz, Z.; Rehman, M.U.; Alsaffar, R.M.; Shah, N.N.; Alshehri, S.; Ghoneim, M.M.; Imam, S.S. MiRNAs in Lung Cancer: Diagnostic, Prognostic, and Therapeutic Potential. Diagnostics (Basel) 2022, 12, doi:10.3390/diagnostics12071610.
56.Mohammadi, C.; Gholamzadeh Khoei, S.; Fayazi, N.; Mohammadi, Y.; Najafi, R. miRNA as promising theragnostic biomarkers for predicting radioresistance in cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2021, 157, 103183, doi:10.1016/j.critrevonc.2020.103183.
57.Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J Clin 2023, 73, 17-48, doi:10.3322/caac.21763.
58.Mundy, G.R. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002, 2, 584-593, doi:10.1038/nrc867.
59.Wu, K.C.; Kao, C.P.; Ho, Y.L.; Chang, Y.S. Quality Control of the Root and Rhizome of Helminthostachys zeylanica (Daodi-Ugon) by HPLC Using Quercetin and Ugonins as Markers. Molecules 2017, 22, doi:10.3390/molecules22071115.


電子全文 電子全文(網際網路公開日期:20280703)
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊