研究生: |
倪楚君 Ni, Chu-jun |
---|---|
論文名稱: |
探討天然皂苷重樓在致癌基因KRAS突變的人類大腸直腸癌細胞造成的合成致死效果 The Saponin Formosanin C-Induced Synthetic Lethalty on Human Colorectal Cancer Cells with Oncogenic KRAS Mutations |
指導教授: |
蘇純立
Su, Chun-Li |
學位類別: |
碩士 Master |
系所名稱: |
人類發展與家庭學系 Department of Human Development and Family Studies |
論文出版年: | 2017 |
畢業學年度: | 105 |
語文別: | 中文 |
論文頁數: | 116 |
中文關鍵詞: | 重樓皂苷 、KRAS突變 、合成致死 、細胞自噬 、細胞凋亡 、粒腺體自噬 |
英文關鍵詞: | Formosanin C, KRAS mutant, Synthetic Lethality, apoptosis, autophagy, mitophagy |
DOI URL: | https://doi.org/10.6345/NTNU202202473 |
論文種類: | 學術論文 |
相關次數: | 點閱:113 下載:1 |
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大約30%的癌症是由於RAS基因突變而成。KRAS是RAS的一種,影響腫瘤的生長和擴散。在大腸直腸癌(Colorectal cancer , CRC)中有30-45%為KRAS突變,但目前未能有針對性治療,導致預後不良。重樓皂苷Formosanin C(FC)是從Rhizoma Paridis saponins (RPS)分離的有效化合物,對肺癌,肝癌和食管癌有抑制作用。本實驗為確定FC是否可以对KRAS基因突變的大腸直腸癌病人有益,使用HT-29 KRAS正常型和HT-29 KRAS突變體兩株細胞。MTT的結果表明,FC對於KRAS突變的細胞抑制效果較佳,可能是FC靶向除KRAS突變型之外的另外一個基因或途徑,增強CRC的細胞毒性,造成合成致死。研究發現KRAS突變細胞產生的自噬狀況较佳,且在抑制劑BAF的預處理的条件下自噬比例明顯下降,證明自噬有走完,但也發現此細胞自噬是保護型的。Annexin V/propidium iodide雙染的結果表明,FC對於KRAS突變細胞產生的凋亡比例較多,没有引起細胞壞死。在抑制細胞自噬之後,會增加更多的細胞凋亡比例。另外, KRAS突變的細胞中FC在48小時可以誘發粒腺體自噬,也是保護性的粒腺體自噬。但KRAS正常的細胞在48小時觀察不到粒腺體自噬,猜測是粒腺體自噬已經走完,因為在西方墨點法中已經沒有Parkin蛋白的表現。綜上所述,在大腸直腸癌細胞中,KRAS突變細胞可透過FC誘發的細胞凋亡引起合成致死,使用細胞自噬粒腺體自噬的抑制劑可加成其效果。
Formosanin C (FC), a component of “Yunnan Bai Yao”, is an anti-cancer compound isolated from Rhizoma Paridis saponins. Colorectal cancer (CRC) is the third most common cause of cancer-related death in Taiwan. The KRAS mutation in colorectal cancers accounts for about 35-45%. KRAS, a RAS isoform, affects the growth and spread of tumor. KRAS mutation failed to target therapies and lead to poor prognosis. To determine whether FC can enhance cytotoxicity of CRC with KRAS mutation, HT-29 KRAS wild-type and HT-29 KRAS mutant cell lines were used. The results of MTT assay indicated that FC induced a stronger dosage-related growth inhibition on HT-29 KRAS mutant than HT-29 KRAS wild-type cells. These data suggest that FC may target one more gene or pathway other than mutant KRAS and thus enhance the cytotoxicity (Synthetic Lethality) of CRC, indicating a critical role of FC on KRAS mutant CRC. In addition, FC induced a higher percentage of cells with acidic vesicular organelles (AVOs, representing an induction of autophagic flux) in HT-29 KRAS mutant cells than HT-29 KRAS wild type cell using flow cytometry. Autophagy inhibitor Bafilomycin A1 (BAF) decreased the percentage of cells with AVOs on both cells. Western blot analysis also showed that FC induced a higher expression of autophagic marker LC-3 II in HT-29 KRAS mutant than HT-29 KRAS wild type cells. Annexin V/propidium iodide double staining analysis showed that both early and late apoptotic cells increased with dosages on both cells, and a stronger apoptosis was triggered on HT-29 KRAS mutant than HT-29 KRAS wild type cells. No induction of necrosis was observed. The immunofluorescence data showed that FC increased the puncta of both Parkin and LC3-II in HT-29 KRAS mutant cells at 48 h of FC treatment. Western blot indicated that no Parkin expression was observed on HT-29 KRAS wild type cells at 48h, suggesting that mitophagy flux maybe completed. Taken together, these data suggest that FC-induced Synthetic Lethality in KRAS mutant cells maybe due to the induction of apoptosis, which maybe reversed by autophagy and mitophagy.
1. Allegra CJ., Jessup JM., Somerfield MR., Hamilton SR., Hammond EH., Hayes DF., McAllister PK., Morton RF., Schilsky RL.. (2009). American Society of Clinical Oncology provisional clinical opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti–epidermal growth factor receptor monoclonal antibody therapy. Journal of Clinical Oncology, 27(12), 2091-2096.
2. André, T., Boni, C., Mounedji-Boudiaf, L., Navarro, M., Tabernero, J., Hickish,T., Hickish,T., Topham,C., Zaninelli,M., Clingan,P., Bridgewater,J., Tabah-Fisch,I., and Gramont, A. (2004). Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. New England Journal of Medicine, 350(23), 2343-2351.
3. Ashford, T. P., & Porter, K. R. (1962). Cytoplasmic components in hepatic cell lysosomes. The Journal of cell biology, 12(1), 198.
4. Ashrafi, G., & Schwarz, T. (2013). The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death & Differentiation, 20(1), 31-42.
5. Bardelli, A., & Siena, S. (2010). Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. Journal of Clinical Oncology, 28(7), 1254-1261.
6. Beaulaton, J., & Lockshin, R. A. (1977). Ultrastructural study of the normal degeneration of the intersegmental muscles of Antheraea polyphemus and Manduca sexta (Insecta, Lepidoptera) with particular reference to cellular autophagy. Journal of Morphology, 154(1), 39-57.
7. Berginc, G., Bračko, M., Ravnik-Glavač, M., & Glavač, D. (2009). Screening for germLine mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome. Familial cancer, 8(4), 421-429.
8. Boland, B., Kumar, A., Lee, S., Platt, F. M., Wegiel, J., Yu, W. H., & Nixon, R. A. (2008). Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. Journal of Neuroscience, 28(27), 6926-6937.
9. Brenner, H., Kloor, M., & Pox, C. P. (2014). Colorectal cancer. The Lancet, 383(9927), 1490-1502. doi:10.1016/s0140-6736(13)61649-9
10. Cui, M., Tang, X., Christian, W. V., Yoon, Y., & Tieu, K. (2010). Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1. Journal of Biological Chemistry, 285(15), 11740-11752.
11. Chen, H.-R., Chuang, Y.-C., Chao, C.-H., & Yeh, T.-M. (2015). Macrophage migration inhibitory factor induces vascular leakage via autophagy. Biology open, 4(2), 244-252.
12. Chen, R. J., Ho, C. T., & Wang, Y. J. (2010). Pterostilbene induces autophagy and apoptosis in sensitive and chemoresistant human bladder cancer cells. Molecular nutrition & food research, 54(12), 1819-1832.
13. Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, Settleman J, Benes CH, Mino-Kenudson M, Wong KK, Engelman JA. (2013). Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell, 23(1), 121-128. doi:10.1016/j.ccr.2012.11.007
14. Cercek, A., & Saltz, L. (2010). Evolving treatment of advanced colorectal cancer. Current oncology reports, 12(3), 153-159.
15. Chen, H.-R., Chuang, Y.-C., Chao, C.-H., & Yeh, T.-M. (2015). Macrophage migration inhibitory factor induces vascular leakage via autophagy. Biology open, 4(2), 244-252.
16. Chen, R. J., Ho, C. T., & Wang, Y. J. (2010). Pterostilbene induces autophagy and apoptosis in sensitive and chemoresistant human bladder cancer cells. Molecular nutrition & food research, 54(12), 1819-1832.
17. Davies, R. J., Miller, R., & Coleman, N. (2005). Colorectal cancer screening: prospects for molecular stool analysis. Nature Reviews Cancer, 5(3), 199-209. doi:10.1038/nrc1569
18. Debnath, J., Baehrecke, E. H., & Kroemer, G. (2005). Does autophagy contribute to cell death? Autophagy, 1(2), 66-74.
19. Degterev, A., & Yuan, J. (2008). Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol, 9(5), 378-390. doi:10.1038/nrm2393
20. Delmas, D., Solary, E., & Latruffe, N. (2011). Resveratrol, a phytochemical inducer of multiple cell death pathways: apoptosis, autophagy and mitotic catastrophe. Current medicinal chemistry, 18(8), 1100-1121.
21. Ding, W.-X., & Yin, X.-M. (2012). Mitophagy: mechanisms, pathophysiological roles, and analysis.
22. Downward, J. (2015). RAS synthetic lethal screens revisited: still seeking the elusive prize? : AACR
23. DPI, D. P. I. INFINITI® KRAS-BRAF Assay.
24. Eid, N., & Kondo, Y. (2017). Parkin in cancer: Mitophagy-related/unrelated tasks. World journal of hepatology, 9(7), 349.
25. Erikson, R. S., & Tedin, K. L. (2015). American public opinion: Its origins, content and impact: Routledge.
26. Foo, J. C. H., Iskandar, K., Yadav, S., & Pervaiz, S. (2016). 274-Targeting of Mutant KRAS Driven Tumors by a Novel Small Molecule is Associated with ROS-Driven Mitophagy and Changes in Mitochondrial Morphology. Free Radical Biology and Medicine, 100, S122.
27. Gewirtz, D. A. (2014). The four faces of autophagy: implications for cancer therapy. Cancer Res, 74(3), 647-651. doi:10.1158/0008-5472.can-13-2966
28. Gonzalez, C. A., & Riboli, E. (2010). Diet and cancer prevention: Contributions from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Eur J Cancer, 46(14), 2555-2562. doi:10.1016/j.ejca.2010.07.025
29. Goss, K. H., & Groden, J. (2000). Biology of the adenomatous polyposis coli tumor suppressor. Journal of Clinical Oncology, 18(9), 1967-1979.
30. Groden J1, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M. (1991). Identification and characterization of the familial adenomatous polyposis coli gene. Cell, 66(3), 589-600.
31. Guo, J. Y., Xia, B., & White, E. (2013). Autophagy-mediated tumor promotion. Cell, 155(6), 1216-1219.
32. Haggar, F. A., & Boushey, R. P. (2009). Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clinics in colon and rectal surgery, 22(04), 191-197.
33. Hsu HC., Thiam TK., Lu YJ., Yeh CY., Tsai WS., You JF., Hung HY., Tsai CN., Hsu A., Chen HC., Chen SJ., Yang TS. (2016). Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients. Oncotarget, 7(16), 22257-22270. doi:10.18632/oncotarget.8076
34. Induces, A. I. (2011). Mitochondrial oxidative stress mediates induction of autophagy and hypertrophy in angiotensin-II treated mouse hearts. Autophagy, 7(8), 917-918.
35. Jerby-Arnon L., Pfetzer N., Waldman YY., McGarry L., James D., Shanks E., Seashore-Ludlow B., Weinstock A., Geiger T., Clemons PA., Gottlieb E., Ruppin E. (2014). Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality. Cell, 158(5), 1199-1209.
36. Jia, Y.-L., Li, J., Qin, Z.-H., & Liang, Z.-Q. (2009). Autophagic and apoptotic mechanisms of curcumin-induced death in K562 cells. Journal of Asian natural products research, 11(11), 918-928.
37. Jin, S. M., & Youle, R. J. (2012). PINK1-and Parkin-mediated mitophagy at a glance. J Cell Sci, 125(4), 795-799.
38. Kaelin, W. G., Jr. (2005). The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer, 5(9), 689-698. doi:10.1038/nrc1691
39. Kane LA., Lazarou M., Fogel AI., Li Y., Yamano K., Sarraf SA., Banerjee S., Youle RJ. (2014). PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol, jcb. 201402104.
40. Kanki, T., Wang, K., Cao, Y., Baba, M., & Klionsky, D. J. (2009). Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Developmental cell, 17(1), 98-109.
41. Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 26(4), 239-257.
42. Kim JH., Kim HY., Lee YK., Yoon YS., Xu WG., Yoon JK., Choi SE., Ko YG., Kim MJ., Lee SJ., Wang HJ., Yoon G.. (2011). Involvement of mitophagy in oncogenic K-Ras-induced transformation: overcoming a cellular energy deficit from glucose deficiency. Autophagy, 7(10), 1187-1198.
43. Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., Yokochi M., Mizuno Y., Shimizu N. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392(6676), 605-608.
44. Kranenburg, O. (2005). The KRAS oncogene: past, present, and future: Elsevier.
45. Lamba S., Russo M., Sun C., Lazzari L., Cancelliere C., Grernrum W., Lieftink C., Bernards R., Di Nicolantonio F., Bardelli A. (2014). RAF suppression synergizes with MEK inhibition in KRAS mutant cancer cells. Cell Rep, 8(5), 1475-1483. doi:10.1016/j.celrep.2014.07.033
46. LamLum H., Ilyas M., Rowan A., Clark S., Johnson V., Bell J., Frayling I., Efstathiou J., Pack K., Payne S., Roylance R., Gorman P., Sheer D., Neale K., Phillips R., Talbot I., Bodmer W., TomLinson I. (1999). The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germLine mutation: a new facet to Knudson's' two-hit'hypothesis. Nature medicine, 5(9), 1071-1075.
47. Lay, J., & Chiang, H. (1980). Saponins from the leaves of Paris formosana. Natural products of higher plants, 1. Planta Medica.
48. Lazarou, M. (2015). Keeping the immune system in check: a role for mitophagy. Immunology and cell biology, 93(1), 3-10.
49. Lee, J., Giordano, S., & Zhang, J. (2012). Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochemical Journal, 441(2), 523-540.
50. Lee, J. C., Su, C. L., Chen, L. L., & Won, S. J. (2009). Formosanin C‐induced apoptosis requires activation of caspase‐2 and change of mitochondrial membrane potential. Cancer science, 100(3), 503-513.
51. Lemasters, J. J. (2005). Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation research, 8(1), 3-5.
52. Levin B., Lieberman DA., McFarland B., Andrews KS., Brooks D., Bond J., Dash C., Giardiello FM., Glick S., Johnson D., Johnson CD., Levin TR., Pickhardt PJ., Rex DK., Smith RA., Thorson A.(2008). Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi‐Society Task Force on Colorectal Cancer, and the American College of Radiology. CA: a cancer journal for clinicians, 58(3), 130-160.
53. Li GB., Fu RQ., Shen HM., Zhou J., Hu XY., Liu YX., Li YN., Zhang HW., Liu X., Zhang YH., Huang C., Zhang R., Gao N. (2017). Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels. Oncotarget, 8(6), 10359.
54. LI, M. C., KOO, W.-Y., & HSU, K.-P. (1972). Anti-neoplastic property of a crude extract from Paris formosana. Nature, 235(59), 223-224.
55. Li, Y., Man, S., Li, J., Chai, H., Fan, W., Liu, Z., & Gao, W. (2014). The antitumor effect of formosanin C on HepG2 cell as revealed by 1 H-NMR based metabolic profiling. Chem Biol Interact, 220, 193-199.
56. Liu, J., & Debnath, J. (2016). The Evolving, Multifaceted Roles of Autophagy in Cancer. Adv Cancer Res, 130, 1-53. doi:10.1016/bs.acr.2016.01.005
57. Lord, C. J., Tutt, A. N., & Ashworth, A. (2015). Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors. Annu Rev Med, 66, 455-470. doi:10.1146/annurev-med-050913-022545
58. Lynch, H. T., Smyrk, T., & Lynch, J. F. (1996). Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome). International journal of cancer, 69(1), 38-43.
59. Makin, G., & Dive, C. (2003). Recent advances in understanding apoptosis: new therapeutic opportunities in cancer chemotherapy. Trends Mol Med, 9(6), 251-255.
60. Man, S., Gao, W., Zhang, Y., Liu, Z., Yan, L., Huang, L., & Liu, C. (2011). Formosanin C-inhibited pulmonary metastasis through repression of matrix metalloproteinases on mouse lung adenocarcinoma. Cancer biology & therapy, 11(6), 592-598.
61. Martin, S. J., & Green, D. R. (1995). Protease activation during apoptosis: death by a thousand cuts? Cell, 82(3), 349-352.
62. McGrath, J. P., Capon, D. J., Smith, D. H., Chen, E. Y., Seeburg, P. H., Goeddel, D. V., & Levinson, A. D. (1983). Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene.
63. McLornan, D. P., List, A., & Mufti, G. J. (2014). Applying synthetic lethality for the selective targeting of cancer. N Engl J Med, 371(18), 1725-1735. doi:10.1056/NEJMra1407390
64. Mirzayans, R., Andrais, B., Scott, A., & Murray, D. (2012). New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy. BioMed Research International, 2012.
65. Moreau, L.-C., Rajan, R., Thirlwell, M. P., & Alcindor, T. (2013). Response to chemotherapy in metastatic colorectal cancer after exposure to oxaliplatin in the adjuvant setting. Anticancer research, 33(4), 1765-1768.
66. Misra, A., Rai, S., & Misra, D. (2016). Functional role of apoptosis in oral diseases: An update. Journal of oral and maxillofacial pathology: JOMFP, 20(3), 491.
67. Narendra, D., Tanaka, A., Suen, D.-F., & Youle, R. J. (2008). Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. The Journal of cell biology, 183(5), 795-803.
68. Nishida, K., Yamaguchi, O., & Otsu, K. (2008). Crosstalk between autophagy and apoptosis in heart disease. Circ Res, 103(4), 343-351. doi:10.1161/circresaha.108.175448
69. Nistal, E., Fernandez-Fernandez, N., Vivas, S., & Olcoz, J. L. (2015). Factors Determining Colorectal Cancer: The Role of the Intestinal Microbiota. Front Oncol, 5, 220. doi:10.3389/fonc.2015.00220
70. Ouakrim, D. A., Lockett, T., Boussioutas, A., Hopper, J. L., & Jenkins, M. A. (2013). Screening participation for people at increased risk of colorectal cancer due to family history: a systematic review and meta-analysis. Familial cancer, 12(3), 459-472.
71. Ouyang, L., Shi, Z., Zhao, S., Wang, F. T., Zhou, T. T., Liu, B., & Bao, J. K. (2012). Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif, 45(6), 487-498. doi:10.1111/j.1365-2184.2012.00845.x
72. Ouyang, L., Shi, Z., Zhao, S., Wang, F. T., Zhou, T. T., Liu, B., & Bao, J. K. (2012). Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell proliferation, 45(6), 487-498.
73. Paglin S., Hollister T., Delohery T., Hackett N., McMahill M., Sphicas E., Domingo D., Yahalom J. (2001). A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer research, 61(2), 439-444.
74. Peltomaki, P. (2001). Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet, 10(7), 735-740.
75. Polewska, J. (2012). [Autophagy--molecular mechanism, apoptosis and cancer]. Postepy Hig Med Dosw (Online), 66, 921-936. doi:10.5604/17322693.1021109
76. Popescu, N., Amsbaugh, S., DiPaolo, J., Tronick, S., Aaronson, S., & Swan, D. (1985). Chromosomal localization of three humanras genes by in situ molecular hybridization. Somatic cell and molecular genetics, 11(2), 149-155.
77. Kinzler KW., Nilbert MC., Su LK., Vogelstein B., Bryan TM., Levy DB., Smith KJ., Preisinger AC., Hedge P., McKechnie D. (1991). Identification of FAP locus genes from chromosome 5q21. Science, 253, 661-665.
78. Prenen, H., Tejpar, S., & Van Cutsem, E. (2010). New strategies for treatment of KRAS mutant metastatic colorectal cancer. Clin Cancer Res, 16(11), 2921-2926. doi:10.1158/1078-0432.ccr-09-2029
79. Proskuryakov, S. Y., Konoplyannikov, A. G., & Gabai, V. L. (2003). Necrosis: a specific form of programmed cell death? Exp Cell Res, 283(1), 1-16.
80. Qi, Y., Qiu, Q., Gu, X., Tian, Y., & Zhang, Y. (2016). ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Scientific reports, 6.
81. Ravikumar, P., Hammesfahr, P., & Sih, C. J. (1979). Cytotoxic saponins from the Chinese herbal drug Yunnan Bai Yao. Journal of pharmaceutical sciences, 68(7), 900-903.
82. Roy, S., & Debnath, J. (2010). Autophagy and tumorigenesis. Semin Immunopathol, 32(4), 383-396. doi:10.1007/s00281-010-0213-0
83. Santoni-Rugiu, E., Falck, J., Mailand, N., Bartek, J., & Lukas, J. (2000). Involvement of Myc activity in a G1/S-promoting mechanism parallel to the pRb/E2F pathway. Molecular and cellular biology, 20(10), 3497-3509.
84. Schernhammer ES., Laden F., Speizer FE., Willett WC., Hunter DJ., Kawachi I., Fuchs CS., Colditz GA. (2003). Night-shift work and risk of colorectal cancer in the nurses’ health study. Journal of the National Cancer Institute, 95(11), 825-828.
85. Sieber, O. M., TomLinson, I. P., & LamLum, H. (2000). The adenomatous polyposis coli (APC) tumour suppressor–genetics, function and disease. Molecular medicine today, 6(12), 462-469.
86. Siegel, R. L., Miller, K. D., & Jemal, A. (2015). Cancer statistics, 2015. CA: a cancer journal for clinicians, 65(1), 5-29.
87. Soravia, C., Bapat, B., & Cohen, Z. (1997). Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC): a review of clinical, genetic and therapeutic aspects. Schweizerische Medizinische Wochenschrift, 127(16), 682-690.
88. Stintzing, S. (2014). Management of colorectal cancer. F1000Prime Rep, 6, 108. doi:10.12703/P6-108
89. Sullivan, K. M., & Kozuch, P. S. (2011). Impact of KRAS mutations on management of colorectal carcinoma. Pathology research international, 2011.
90. Sun, S. Y. (2011). Understanding the Role of the Death Receptor 5/FADD/caspase-8 Death Signaling in Cancer Metastasis. Mol Cell Pharmacol, 3(1), 31-34.
91. Tappenden, P., Jones, R., Paisley, S., & Carroll, C. (2007). The cost-effectiveness of bevacizumab in the first-line treatment of metastatic colorectal cancer in England and Wales. European journal of cancer, 43(17), 2487-2494.
92. Taylor, D. P., Burt, R. W., Williams, M. S., Haug, P. J., & Cannon–Albright, L. A. (2010). Population-based family history–specific risks for colorectal cancer: a constellation approach. Gastroenterology, 138(3), 877-885.
93. Temraz, S., Mukherji, D., & Shamseddine, A. (2015). Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers. Int J Mol Sci, 16(9), 22976-22988. doi:10.3390/ijms160922976
94. Tolkovsky, A. M. (2009). Mitophagy. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1793(9), 1508-1515.
95. Triantafillidis, J. K., Nasioulas, G., & Kosmidis, P. A. (2009). Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res, 29(7), 2727-2737.
96. Valente EM., Abou-Sleiman PM., Caputo V., Muqit MM., Harvey K., Gispert S., Ali Z., Del Turco D., Bentivoglio AR., Healy DG., Albanese A., Nussbaum R., González-Maldonado R., Deller T., Salvi S., Cortelli P., Gilks WP., Latchman DS., Harvey RJ., Dallapiccola B., Auburger G., Wood NW. (2004). Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 304(5674), 1158-1160.
97. Eric Van Cutsem.,I Lang., G D’Haens., V Moiseyenko.,J Zaluski., G Folprecht., S Tejpar.,J Nippgen., C Stroh., P Rougier. (2008) KRAS status and efficacy in the CRYSTAL study: firstline treatment of patients with metastatic colorectal cancer receiving FOLFIRI with or without cetuximab. European Society of Medical Oncology Meeting. Annals of oncology, 19.
98. Vasen HF., Möslein G., Alonso A., Aretz S., Bernstein I., Bertario L., Blanco I., Bülow S., Burn J., Capella G., Colas C., Engel C., Frayling I., Friedl W., Hes FJ., Hodgson S., Järvinen H., Mecklin JP., Møller P., Myrhøi T., Nagengast FM., Parc Y., Phillips R., Clark SK., de Leon MP., Renkonen-Sinisalo L., Sampson JR., Stormorken A., Tejpar S., Thomas HJ., Wijnen J. (2008). Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut, 57(5), 704-713.
99. Vives-Bauza, C., & Przedborski, S. (2011). Mitophagy: the latest problem for Parkinson's disease. Trends in molecular medicine, 17(3), 158-165.
100. Warburg, O. (1920). Über die Reduktion der Salpetersäure in grünen Zellen. Naturwissenschaften, 8(30), 594-596.
101. Welman, A., Burger, M. M., & Hagmann, J. (2000). Structure and function of the C-terminal hypervariable region of K-Ras4B in plasma membrane targetting and transformation. Oncogene, 19(40), 4582.
102. Wen, X., Lin, Z. Q., Liu, B., & Wei, Y. Q. (2012). Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer. Cell Prolif, 45(3), 217-224. doi:10.1111/j.1365-2184.2012.00814.x
103. West, N. P., Hohenberger, W., Weber, K., Perrakis, A., Finan, P. J., & Quirke, P. (2010). Complete mesocolic excision with central vascular ligation produces an oncologically superior specimen compared with standard surgery for carcinoma of the colon. J Clin Oncol, 28(2), 272-278. doi:10.1200/JCO.2009.24.1448
104. Willett, W. C., Stampfer, M. J., Colditz, G. A., Rosner, B. A., & Speizer, F. E. (1990). Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. New England Journal of Medicine, 323(24), 1664-1672.
105. Winawer S., Fletcher R., Rex D., Bond J., Burt R., Ferrucci J., Ganiats T., Levin T., Woolf S., Johnson D., Kirk L., Litin S., Simmang C. (2003). Colorectal cancer screening and surveillance: clinical guidelines and rationale—update based on new evidence. Gastroenterology, 124(2), 544-560.
106. Wu, R.-T., Chiang, H.-C., Fu, W.-C., Chien, K.-Y., Chung, Y.-M., & Horng, L.-Y. (1990). Formosanin-C, an immunomodulator with antitumor activity. International journal of immunopharmacology, 12(7), 777-786.
107. Wu, R.-T., Lin, W.-J., Chiang, H.-C., Horng, L.-Y., & Chung, Y.-M. (1990). Modulation of experimental autoimmune uveitis with formosanin-C in guinea pigs. Journal of Ocular Pharmacology and Therapeutics, 6(4), 301-311.
108. Xavier, C. P., Lima, C. F., Preto, A., Seruca, R., Fernandes-Ferreira, M., & Pereira-Wilson, C. (2009). Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells. Cancer letters, 281(2), 162-170.
109. Yang, M., Zou, J., Zhu, H., Liu, S., Wang, H., Bai, P., & Xiao, X. (2015). Paris saponin II inhibits human ovarian cancer cell‑induced angiogenesis by modulating NF-κB signaling. Oncology reports, 33(5), 2190-2198.
110. Yuille, A. L., & Rangarajan, A. (2002). The concave-convex procedure (CCCP). Paper presented at the Advances in neural information processing systems.
111. Zhang, S.-M., Shang, Z.-F., & Zhou, P.-K. (2015). Autophagy as the effector and player in DNA damage response of cells to genotoxicants. Toxicology Research, 4(3), 613-622.
112. Ziemke EK., Dosch JS., Maust JD., Shettigar A., Sen A., Welling TH., Hardiman KM., Sebolt-Leopold JS. (2016). Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6. Clin Cancer Res, 22(2), 405-414. doi:10.1158/1078-0432.CCR-15-0829