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系統識別號 U0026-2407201709213400
論文名稱(中文) KRAS Gene Mutations在大腸直腸癌肝轉移中扮演的角色
論文名稱(英文) The Role of KRAS Gene Mutations in Colon Cancer with Liver Metastasis
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 105
學期 2
出版年 106
研究生(中文) 林鵬展
研究生(英文) Peng-Chan Lin
學號 S98961018
學位類別 博士
語文別 英文
論文頁數 146頁
口試委員 指導教授-李政昌
指導教授-呂增宏
口試委員-蘇五洲
口試委員-洪澤民
口試委員-江伯敏
口試委員-陳立宗
口試委員-王照元
口試委員-張金堅
中文關鍵字 大腸直腸癌  肝轉移  KRAS 基因突變 
英文關鍵字 Colorectal cancer  Liver metastasis  KRAS gene mutations 
學科別分類
中文摘要 大腸直腸癌(Colorectal Cancer)是台灣癌症相關的發生率第一名和死亡率的第二大原因。即使患者在接受盡可能的根除性手術治療和輔助性的化學治療,仍有超過50%的的病人會復發並最終死於肝臟轉移性疾病。因此,了解腫瘤發生復發及識別預後的相關原因在大腸直腸癌的患者中的扮演關鍵的重要角色而且是重要的。會發生肝臟轉移的大腸直腸癌的患者涉及許多因素,包括腫瘤的微環境,具有轉移相關基因,具有生長因子及接受體,含有趨化因子,細胞週期調節失控等因素。
在這項研究中,首先,我們在臨床上發現KRAS基因突變是大腸直腸癌腫瘤進展和肝轉移具有相關聯的生物標記。我們利用等位基因鑑別方法檢測大腸直腸腫瘤中的KRAS基因的突變。證明,KRAS基因的突變與大腸直腸肝轉移的臨床患者預後不良相關。之後,我們進一步建了KRAS基因突變於大腸直腸癌腫瘤肝轉移的生物模型,動物模型,臨床組織中YB-1和IGF-1R的表達相關聯和肝轉移的關係。我們證實了KRAS基因突變調控了YB-1及其下游IGF-IR表達的證據。基於此發現,我們建立了致癌性KRAS驅動腫瘤侵襲性和肝轉移的模型。接下來我們利用患者的臨床資料及組織樣本,評估並找尋大腸直腸肝轉移的KRAS基因突變相關標記的表現和預後的關係。我們發現CDK1的去磷酸化pTyr15(KRAS突變基因可以在細胞週期進程中激活CDK1通過pThr161)會導致癌細胞轉移,CD151(信號可能負調節RAS-ERK / MAPK信號通路)會在轉移後重新產生。環氧合酶-2(COX-2,重要的突變RAS靶基因)表現狀態和患者生存的有關聯。KRAS突變基因相關因子會影響腫瘤微環境因子(COX2),轉移相關的細胞粘附分子(CD151)和細胞週期調節因子(CDK1)等多種因素。
因此,我們得出結論,KRAS基因突變與大腸直腸肝轉移的轉移進展相關。 KRAS基因突變肝轉移的模型提供了使用MEK抑製劑作治療的機轉和理由,用於防止在KRAS基因突變型大結直腸癌患者接受肝切除術後的復發。
英文摘要 Colorectal cancer (CRC) is the leading causes of cancer-related morbidity and mortality in Taiwan. Even in patients with CRC who receive potentially curative surgery and adjuvant chemotherapy, more than 50% relapse and ultimately die from metastatic disease. It is, therefore, important to identify prognostic makers and understand the key role of tumorigenesis in patients with CRC.CRC with liver metastasis involve many factors, including tumor microenvironment, metastasis associated genes, growth factors, chemokines, receptors, and cellular adhesion molecules, and cell cycle regulator.
In this project, firstly, I show that the mutation KRAS gene is a potential marker for tumor progression and liver metastasis in colorectal cancer. I detect KRAS gene mutation in colorectal tumors by the allele discrimination method. I also proof that KRAS mutations correlate with poor prognosis for colorectal liver metastases in clinical patients. Secondary, we link between mutant KRAS and the expression of YB-1 and IGF-IR in different CRC cell lines, animal models, clinical cancer tissue. In this study, we obtained evidence indicating that KRAS up-regulates the expression of YB-1 and its downstream target IGF-IR. Based on this finding, we reported that oncogenic KRAS drives tumor aggressiveness and liver metastasis. Thirdly, we also show that CDK1 Ptyr15 dephosphorylation (KRAS mutation gene can activated CDK1 in cell cycle progression via pThr161) in metastatic cancer patients, dynamic CD151 changes (signaling might negatively regulate RAS–ERK/MAPK signaling pathway) in liver metastasis tissue, the expression of cyclooxygenase-2 (COX-2, an important mutation RAS target gene) in cancer patients. KRAS gene mutations are associated with many factors including tumor microenvironment (COX2), metastasis, cellular adhesion molecules(CD151), and cell cycle regulator(CDK1) which can affect CRC survival.
So, we conclude that KRAS mutation is correlated with tumor aggressiveness in patients with colorectal liver metastases. The identification of this KRAS-driven pathway provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection.
論文目次 Chapter 1: Background and Introduction
1.1 Mutation KRAS Genes Are Associated with Tumor Progression and Liver Metastasis in Colorectal Cancer…………………………………………………...1
1.1.1 KRAS Gene Mutations and Detection Method………………………….…….1
1.1.2 KRAS Gene Mutations in Colon Cancer with Liver Metastasis…………...….2
1.1.3 Mechanism of KRAS Mutation-Drive Tumor Progression and Liver
Metastasis in Colorectal Cancer……………………………………………...3
1.2 Molecular Biology of KRAS Mutation Genes Associated Signaling Pathway …..4
1.2.1 KRAS Gene Mutations Regulate CDK1 phosphorylated on Thr-161………...4
1.2.2 CD151 Expressions Negatively Regulate KRAS signally pathway………..…4
1.2.3 Mutant KRAS Upregulate COX2 Expression…………………………………5
1.3 Figures and Tables………………………………………………………………...7
Chapter 2: KRAS Gene Mutations and Detection Method
2.1 Background and Introduction…………………………………………………….10
2.2 Material and Methods…………………………………………………………….11
2.3 Results……………………………………………………………………………13
2.4 Discussion and Conclusion……………………………………………………....17
2.5 Figures and Tables……………………………………………………………….22
Chapter 3: KRAS Gene Mutations in Colon Cancer with Liver Metastasis
3.1 Background and Introduction…………………………………………………….31
3.2 Material and Methods…………………………………………………………….31
3.3 Results……………………………………………………………………………35
3.4 Discussion and Conclusion………………………………………………………36
3.5 Figures and Tables……………………………………………………………….40
Chapter 4: Mechanism of KRAS Mutation-Drive Tumor Progression and Liver Metastasis in Colorectal Cancer
4.1 Background and Introduction…………………………………………………….46
4.2 Material and Methods…………………………………………………………….47
4.3 Results……………………………………………………………………………49
4.4 Discussion and Conclusion………………………………………………………51
4.5 Figures and Tables……………………………………………………………….53
Chapter 5: Tyrosine Phosphorylation Cyclin-Dependent Kinase 1 Associates with Colorectal Cancer Survival
5.1 Background and Introduction…………………………………………………….57
5.2 Material and Methods…………………………………………………………….58
5.3 Results……………………………………………………………………………65
5.4 Discussion and Conclusion………………………………………………………73
5.5 Figures and Tables……………………………………………………………….74
Chapter 6: The Role of CD151 Expression in Colorectal Cancer with liver Metastasis
6.1 Background and Introduction…………………………………………………….83
6.2 Material and Methods…………………………………………………………….84
6.3 Results……………………………………………………………………………87
6.4 Discussion and Conclusion………………………………………………………89
6.5 Figures and Tables……………………………………………………………….93
Chapter 7: The Role of COX2 Expression in Colorectal Cancer
7.1 Background and Introduction…………………………………………………...100
7.2 Material and Methods…………………………………………………………...102
7.3 Results…………………………………………………………………………..104
7.4 Discussion and Conclusion……………………………………………………..107
7.5 Figures and Tables……………………………………………………………...111
Chapter 8: Conclusion……………………………………...……………………….121
References……………………………………………………………………..……122


參考文獻 1. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev. 2003;3:7-13.
2. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev. 2003;3:11-22.
3. Ian A. Prior, Paul D. Lewis, and Carla Mattos.A comprehensive survey of RAS mutations in cancer.Cancer Res. 2012 May 15; 72(10): 2457–2467.
4. Marchetti A, Gasparini G. 2009. KRAS mutations and cetuximab in colorectal cancer. N Engl J Med 360:833–834. Author reply 835–836.
5. Poehlmann AKD, Meyer F, Lippert H, Roessner A, Schneider-Stock R.2007. K-RAS mutation detection in colorectal cancer using pyrosequencing technique. Pathol Res Pract 203:489–497.
6. Kypros Zenonos and Katy Kyprianou.RAS signaling pathways, mutations and their role in colorectal cancer. World J Gastrointest Oncol. 2013 May 15; 5(5): 97–101.
7. Bos J. L. (1989) Cancer Res. 49:4682–4689.
8. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–345.
9. Grothey A, Sargent DJ. FOLFOX for stage II colon cancer? A commentary on the recent FDA approval of oxaliplatin for adjuvant therapy of stage III colon cancer. Journal of Clinical Oncology 2005;23:3311-3313.
10. Sadahiro S, Suzuki T, Ishikawa K, et al. Recurrence patterns after curative resection of colorectal cancer in patients followed for a minimum of ten years. Hepato-Gastroenterology 2003;50:1362-1366.
11. Rees M, Tekkis PP, Welsh FKS, O'Rourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer - A multifactorial model of 929 patients. Annals of Surgery 2008;247:125-135.
12. Iwatsuki S, Dvorchik I, Madariaga JR, et al. Hepatic resection for metastatic colorectal adenocarcinoma: A proposal of a prognostic scoring system. Journal of the American College of Surgeons 1999;189:291-299.
13. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic Alterations During Colorectal-Tumor Development. New England Journal of Medicine 1988;319:525-532.
14. Andreyev HJN, Norman AR, Cunningham D, et al. Kirsten RAS mutations in patients with colorectal cancer: the 'RASCAL II' study. British Journal of Cancer 2001;85:692-696.
15. Ahnen DJ, Feigl P, Quan G, et al. Ki-RAS mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Research 1998;58:1149-1158.
16. Lievre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. Journal of Clinical Oncology 2008;26:374-379.
17. Nash GM, Gimbel M, Shia J, et al. KRAS Mutation Correlates With Accelerated Metastatic Progression in Patients With Colorectal Liver Metastases. Annals of Surgical Oncology 2010;17:572-578.
18. Lasham, A., Lindridge, E., Rudert, F., Onrust, R. and Watson, J. (2000) Regulation of the human fas promoter by YB-1, Puralpha and AP-1 transcription factors. Gene, 252, 1-13.
19. Lasham, A., Moloney, S., Hale, T., Homer, C., Zhang, Y.F., Murison, J.G., Braithwaite, A.W. and Watson, J. (2003) The Y-box-binding protein, YB1, is a potential negative regulator of the p53 tumor suppressor. J Biol Chem, 278, 35516-35523.
20. Homer, C., Knight, D.A., Hananeia, L., Sheard, P., Risk, J., Lasham, A., Royds, J.A. and Braithwaite, A.W. (2005) Y-box factor YB1 controls p53 apoptotic function. Oncogene, 24, 8314-8325.
21. Wu, J., Lee, C., Yokom, D., Jiang, H., Cheang, M.C., Yorida, E., Turbin, D., Berquin, I.M., Mertens, P.R., Iftner, T. et al. (2006) Disruption of the Y-box binding protein-1 results in suppression of the epidermal growth factor receptor and HER-2. Cancer Res, 66, 4872-4879.
22. En-Nia, A., Yilmaz, E., Klinge, U., Lovett, D.H., Stefanidis, I. and Mertens, P.R. (2005) Transcription factor YB-1 mediates DNA polymeRASe alpha gene expression. J Biol Chem, 280, 7702-7711.
23. Das, S., Chattopadhyay, R., Bhakat, K.K., Boldogh, I., Kohno, K., PRASad, R., Wilson, S.H. and Hazra, T.K. (2007) Stimulation of NEIL2-mediated oxidized base excision repair via YB-1 interaction during oxidative stress. J Biol Chem, 282, 28474-28484.
24. Goldsmith, M.E., Madden, M.J., Morrow, C.S. and Cowan, K.H. (1993) A Y-box consensus sequence is required for basal expression of the human multidrug resistance (mdr1) gene. J Biol Chem, 268, 5856-5860.
25. Stein, U., Jurchott, K., Walther, W., Bergmann, S., Schlag, P.M. and Royer, H.D. (2001) Hyperthermia-induced nuclear translocation of transcription factor YB-1 leads to enhanced expression of multidrug resistance-related ABC transporters. J Biol Chem, 276, 28562-28569.
26. Evdokimova, V., Tognon, C., Ng, T., Ruzanov, P., Melnyk, N., Fink, D., Sorokin, A., Ovchinnikov, L.P., Davicioni, E., Triche, T.J. et al. (2009) Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition. Cancer Cell, 15, 402-415.
27. Mertens, P.R., Harendza, S., Pollock, A.S. and Lovett, D.H. (1997) Glomerular mesangial cell-specific transactivation of matrix metalloproteinase 2 transcription is mediated by YB-1. J Biol Chem, 272, 22905-22912.
28. Shibao, K., Takano, H., Nakayama, Y., Okazaki, K., Nagata, N., Izumi, H., Uchiumi, T., Kuwano, M., Kohno, K. and Itoh, H. (1999) Enhanced coexpression of YB-1 and DNA topoisomeRASe II alpha genes in human colorectal carcinomas. Int J Cancer, 83, 732-737.
29. Toulany, M., Schickfluss, T.A., Eicheler, W., Kehlbach, R., Schittek, B. and Rodemann, H.P. (2011) Impact of oncogenic K-RAS on YB-1 phosphorylation induced by ionizing radiation. Breast Cancer Res, 13, R28.
30. Fung T. K., Poon R. Y. 2005. A roller coaster ride with the mitotic cyclins. Semin. Cell Dev. Biol. 16:335–342.
31. Kubiak JZ1, Ciemerych MA, Hupalowska A.On the transition from the meiotic to mitotic cell cycle during early mouse development. Int J Dev Biol. 2008;52(2-3):201-17.
32. Costa-Cabral S, Brough R, Konde A, Aarts M, Campbell J, et al. (2016) Correction: CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours. PLOS ONE 11(4): e0154007.
33. Charrin, S., Latil, M., Soave, S., Polesskaya, A., Chre´ tien, F., Boucheix, C. and Rubinstein, E. (2013). Normal muscle regeneration requires tight control of muscle cell fusion by tetRASpanins CD9 and CD81. Nat. Commun. 4, 1674.
34. Codina, J., Li, J. and Dubose, T. D., Jr (2005). CD63 interacts with the carboxy terminus of the colonic H+-K+-ATPase to decrease (corrected) plasma membrane localization and 86Rb+ uptake. Am. J. Physiol. 288, C1279-C1286.
35. Copeland, B. T., Bowman, M. J. and Ashman, L. K. (2013a). Genetic ablation of the tetRASpanin CD151 reduces spontaneous metastatic spread of prostate cancer in the TRAMP model. Mol. Cancer Res. 11, 95-105.
36. Rafal Sadej, Alicja Grudowska, Lukasz Turczyk, Radzislaw Kordek and Hanna M Romansk. CD151 in cancer progression and metastasis: a complex scenario. Laboratory Investigation (2014) 94, 41–51.
37. Martin E. Hemler. Tetraspanin functions and associated microdomains. Nature Reviews Molecular Cell Biology 6, 801-811 (October 2005).
38. Subbaramaiah K., Telang N., Ramonetti J. T., Araki R., DeVito B., Weksler B. B., Dannenberg A. J. (1996) Cancer Res. 56:4424–4429.
39. Sheng G. G., Shao J., Sheng H., Hooton E. B., Isakson P. C., Morrow J. D., Coffey R. J., DuBois R. N., Beauchamp R. D. (1997) Gastroenterology 113:1883–1891.
40. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107:1183-8.
41. Sheng, H., Williams, C.S., Shao, J., Liang, P., DuBois, R.N., and Beauchamp, R.D. (1998). Induction of cyclooxygenase-2 by activated Ha-RAS oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway.J. Biol. Chem. 273, 22120–22127.
42. Hoang, B., Zhu, L., Shi, Y., Frost, P., Yan, H., Sharma, S., Sharma, S., Goodglick, L., Dubinett, S., and Lichtenstein, A. (2006). Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance. Blood 107, 4484–4490.
43. Grabocka, Elda et al. Mutant KRAS Enhances Tumor Cell Fitness by Upregulating Stress Granules. Cell , Volume 167 , Issue 7 , 1803 - 1813.e12.
44. Pham, H., Eibl, G., Vincenti, R., Chong, B., Tai, H.H., and Slice, L.W. (2008).15-Hydroxyprostaglandin dehydrogenase suppresses KRASV12-dependent tumor formation in Nu/Nu mice. Mol. Carcinog. 47, 466–477.
45. Brink M, de Goeij AF, Weijenberg MP, Roemen GM, Lentjes MH, Pachen MM, Smits KM, de Bruine AP, Goldbohm RA, van den Brandt PA. 2003. KRAS oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis 24:703–710.
46. Kobunai T, Watanabe T, Yamamoto Y, Eshima K. 2010. The frequency of KRAS mutation detection in human colon carcinoma is influenced by the sensitivity of assay methodology: A comparison between direct sequencing and real-time PCR. Biochem Biophys Res Commun 395:158–162.
47. Lihui Chow, Peng-Chan Lin, Jeffrey S. Chang, Pei-Yi Chu, Pao-Kung Lee, Shan-Na Chen, Ying-Min Cheng, Jenq-Chang Lee, Jang-Yang Chang and Tsang-Wu Liu. Differences in the frequencies of K-ras c12–13 genotypes by gender and pathologic phenotypes in colorectal tumors measured using the allele discrimination method( Article first published online: 25 AUG 2011)
48. Ohnishi T, Tomita N, Monden T, Ohue M, Yana I, Takami K, Yamamoto H, Yagyu T, Kikkawa N, Shimano T, Monden M. 1997. A detailed analysis of the role of KRAS gene mutation in the progression of colorectal adenoma. Br J Cancer 75:341–347.
49. Li CF, Huang WW, Wu JM, Yu SC, Hu TH, Uen YH, Tian YF, Lin CN, Lu D, Fang FM, Huang HY. 2008. Heat shock protein 90 overexpression independently predicts inferior disease-free survival with differential expression of the alpha and beta isoforms in gastrointestinal stromal tumors. Clin Cancer Res 14:7822–7831.
50. Do H, Krypuy M, Mitchell PL, Fox SB, Dobrovic A. 2008. High resolution melting analysis for rapid and sensitive EGFR and KRAS mutation detection in formalin fixed paraffin embedded biopsies. BMC Cancer 8:142.
51. Lee JC, Wang ST, Lai MD, Lin YJ, Yang HB. 1996. KRAS gene mutation is a useful predictor of the survival of early stage colorectal cancers. Anticancer Res 16:3839–3844.
52. Wang JY, Hsieh JS, Chen FM, Yeh CS, Alexandersen K, Huang TJ,Chen D, Lin SR. 2003. High frequency of activated KRAS codon 15 mutant in colorectal carcinomas from Taiwanese patients. Int J Cancer 107:387–393.
53. Wang JY, Hsieh JS, Lu CY, Yu FJ, Wu JY, Chen FM, Huang CJ, Lin SR. 2007. The differentially mutational spectra of the APC, KRAS,and p53 genes in sporadic colorectal cancers from Taiwanese patients. Hepatogastroenterology 54:2259–2265.
54. Gallegos Ruiz MI, Floor K, Rijmen F, Grunberg K, Rodriguez JA, Giaccone G. 2007. EGFR and KRAS mutation analysis in non-small cell lung cancer: Comparison of paraffin embedded versus frozen specimens. Cell Oncol 29:257–264.
55. Al-Mulla F, Going JJ, Sowden ET, Winter A, Pickford IR, Birnie GD. 1998. Heterogeneity of mutant versus wild-type Ki-RAS in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality. J Pathol 185:130–138.
56. Baisse B, Bouzourene H, Saraga EP, Bosman FT, Benhattar J. 2001. Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma. Int J Cancer 93:346–352.
57. Losi L, Baisse B, Bouzourene H, Benhattar J. 2005. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 26:916–922.
58. Bazan V, Migliavacca M, Zanna I, Tubiolo C, GRASsi N, Latteri MA, La Farina M, Albanese I, Dardanoni G, Salerno S, Tomasino RM, Labianca R, Gebbia N, Russo A. 2002. Specific codon 13 KRAS mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 KRAS mutations are associated with mucinous histotype. Ann Oncol 13:1438–1446.
59. Span M, Moerkerk PT, De Goeij AF, Arends JW. 1996. A detailed analysis of KRAS point mutations in relation to tumor progression and survival in colorectal cancer patients. Int J Cancer (Pred Oncol) 69:241–245.
60. Chang YS, Yeh KT, Chang TJ, Chai C, Lu HC, Hsu NC, Chang JG. 2009. Fast simultaneous detection of KRAS mutations in colorectal cancer. BMC Cancer 9:179.
61. Pajkos G, Kiss I, Sandor J, Ember I, Kishazi P. 2000. The prognostic value of the presence of mutations at the codons 12, 13, 61 of KRAS oncogene in colorectal cancer. Anticancer Res 20:1695–1701.
62. Samowitz WS, Curtin K, Schaffer D, Robertson M, Leppert M, Slattery ML. 2000. Relationship of Ki-RAS mutations in colon cancers to tumor location, stage, and survival: A population-based study. Cancer Epidemiol Biomarkers Prev 9:1193–1197.
63. Abubaker J, Bavi P, Al-Haqawi W, Sultana M, Al-Harbi S, Al-Sanea N,Abduljabbar A, Ashari LH, Alhomoud S, Al-Dayel F, Uddin S, Al-Kuraya KS. 2009. Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J Pathol 219:435–445.
64. Breivik J, Meling GI, Spurkland A, Rognum TO, Gaudernack G. 1994.KRAS mutation in colorectal cancer: Relations to patient age, sex and tumour location. Br J Cancer 69:367–371.
65. Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. 1998. Kirsten RAS mutations in patients with colorectal cancer: The multicenter ‘RASCAL’’ study. J Natl Cancer Inst 90:675–684.
66. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. 2009. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract 205:858–862.
67. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205-16.
68. Chen CY, Shiesh SC, Wu SJ. Rapid detection of KRAS mutations in bile by peptide nucleic acid-mediated PCR clamping and melting curve analysis: comparison with restriction fragment length polymorphism analysis. Clin Chem 2004;50:481-9.
69. Adam R, Wicherts DA, de Haas RJ, Ciacio O, Lévi F, Paule B et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 2009;27:1829-35.
70. De Jong MC, Pulitano C, Ribero D, Strub J, Mentha G, Schulick RD et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg 2009;250:440-8.
71. Goslin R, Steele G, Zamcheck N, Mayer R, Macintyre J. Factors influencing survival in patients with hepatic metastases from adenocarcinoma of the colon or rectum. Dis Colon Rectum 1982;25:749-54.
72. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007;25:4575-80.
73. Choti MA, Sitzmann JV, Tiburi MF, Sumetchotimetha W, Rangsin R, Schulick RD et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235:759-65.
74. Pawlik TM, Izzo F, Cohen DS, Morris JS, Curley SA. Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients. Ann Surg Oncol 2003;10:1059-69.
75. Torzilli G, Donadon M, Palmisano A, Marconi M, Procopio F, Botea F et al. UltRASound guided liver resection: does this approach limit the need for portal vein embolization? Hepatogastroenterology 2009;56:1483-90.
76. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371:1007-16.
77. Kornprat P, Jarnagin WR, Gonen M, DeMatteo RP, Fong Y, Blumgart LH et al. Outcome after hepatectomy for multiple (four or more) colorectal metastases in the era of effective chemotherapy. Ann Surg Oncol 2007;14:1151-60.
78. Lee JC, Wang ST, Chow NH, Yang HB. Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer 2002;38:1065-71.
79. Spano JP, Lagorce C, Atlan D, Milano G, Domont J, Benamouzig R et al. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 2005;16:102-8.
80. Wu Y, Yamada S, Izumi H, Li Z, Shimajiri S, Wang KY, Liu YP, Kohno K, and Sasaguri Y. Strong YB-1 expression is associated with liver metastasis progression and predicts shorter disease-free survival in advanced gastric cancer. J Surg Oncol. 2012;105(7):724-30.
81. Yan X, Yan L, Zhou J, Liu S, Shan Z, Jiang C, Tian Y, and Jin Z. High expression of Y-box-binding protein 1 is associated with local recurrence and predicts poor outcome in patients with colorectal cancer. Int J Clin Exp Pathol. 2014;7(12):8715-23.
82. Sachdev D, and Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007;6(1):1-12.
83. Samani AA, Yakar S, LeRoith D, and Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28(1):20-47.
84. Ewing GP, and Goff LW. The insulin-like growth factor signaling pathway as a target for treatment of colorectal carcinoma. Clin Colorectal Cancer. 2010;9(4):219-23.
85. Vigneri PG, Tirro E, Pennisi MS, Massimino M, Stella S, Romano C, and Manzella L. The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy. Front Oncol. 2015;5(230.
86. Lasham A, Print CG, Woolley AG, Dunn SE, and Braithwaite AW. YB-1: oncoprotein, prognostic marker and therapeutic target? Biochem J. 2013;449(1):11-23.
87. Okamoto K, Ishiguro T, Midorikawa Y, Ohata H, Izumiya M, Tsuchiya N, Sato A, Sakai H, and Nakagama H. miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver. EMBO J. 2012;31(7):1752-63.
88. Ding C, Luo J, Li L, Li S, Yang L, Pan H, Liu Q, Qin H, Chen C, and Feng J. Gab2 facilitates epithelial-to-mesenchymal transition via the MEK/ERK/MMP signaling in colorectal cancer. J Exp Clin Cancer Res. 2016;35(5).
89. Leonard GD, Brenner B, and Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2005;23(9):2038-48.
90. Brudvik KW, Kopetz SE, Li L, Conrad C, Aloia TA, and Vauthey JN. Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases. Br J Surg. 2015;102(10):1175-83.
91. Passiglia F, Bronte G, Bazan V, Galvano A, Vincenzi B, and Russo A. Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2016;99(150-7.
92. Bennouna J, Lang I, Valladares-Ayerbes M, Boer K, Adenis A, Escudero P, Kim TY, Pover GM, Morris CD, and Douillard JY. A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs. 2011;29(5):1021-8.
93. Lee MS, and Kopetz S. Novel Therapies in Development for Metastatic Colorectal Cancer. Gastrointest Cancer Res. 2014;7(4 Suppl 1):S2-7.
94. Morandell S, Stasyk T, Grosstessner-Hain K, Roitinger E, Mechtler K, Bonn GK, et al. Phosphoproteomics strategies for the functional analysis of signal transduction. Proteomics. 2006; 6(14):4047–56.
95. Gibbs JB, Oliff A. Pharmaceutical research in molecular oncology. Cell. 1994; 79(2):193–8.
96. Mann M, Ong SE, Gronborg M, Steen H, Jensen ON, Pandey A. Analysis of protein phosphorylation using mass spectrometry: deciphering the phosphoproteome. Trends Biotechnol. 2002; 20(6):261–8.
97. Nita-Lazar A, Saito-Benz H, White FM. Quantitative phosphoproteomics by mass spectrometry: past, present, and future. Proteomics. 2008; 8(21):4433–43.
98. Talamonti MS, Roh MS, Curley SA, Gallick GE. Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. J Clin Invest. 1993; 91(1):53–60.
99. McKinley ET, Liu H, McDonald WH, Luo W, Zhao P, Coffey RJ, et al. Global phosphotyrosine proteomics identifies PKCdelta as a marker of responsiveness to Src inhibition in colorectal cancer. PLoS One. 2013; 8(11):e80207.
100. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007; 131(6):1190–203
101. Wolf-Yadlin A, Kumar N, Zhang Y, Hautaniemi S, Zaman M, Kim HD, et al. Effects of HER2 overexpression on cell signaling networks governing proliferation and migration. Mol Syst Biol. 2006; 2:54
102. Kettenbach AN, Gerber SA. Rapid and reproducible single-stage phosphopeptide enrichment of complex peptide mixtures: application to general and phosphotyrosine-specific phosphoproteomics experiments. Analytical chemistry. 2011; 83(20):7635–44.
103. Wu HY, Tseng VS, Chen LC, Chang YC, Ping P, Liao CC, et al. Combining alkaline phosphatase treatment and hybrid linear ion trap/Orbitrap high mass accuracy liquid chromatography-mass spectrometry data for the efficient and confident identification of protein phosphorylation. Analytical chemistry. 2009; 81(18):7778–87.
104. Ding VM, Boersema PJ, Foong LY, Preisinger C, Koh G, Natarajan S, et al. Tyrosine phosphorylation profiling in FGF-2 stimulated human embryonic stem cells. PLoS One. 2011; 6(3):e17538.
105. Wu HY, Tseng VS, Liao PC. Mining phosphopeptide signals in liquid chromatography-mass spectrometry data for protein phosphorylation analysis. J Proteome Res. 2007; 6(5):1812–21.
106. Wu HY, Tseng VS, Chen LC, Chang HY, Chuang IC, Tsay YG, et al. Identification of tyrosine-phosphorylated proteins associated with lung cancer metastasis using label-free quantitative analyses. J Proteome Res. 2010; 9(8):4102–12.
107. Montoya A, Beltran L, Casado P, Rodriguez-Prados JC, Cutillas PR. Characterization of a TiO(2) enrichment method for label-free quantitative phosphoproteomics. Methods. 2011; 54(4):370–8.
108. Gilmore JM, Kettenbach AN, Gerber SA. Increasing phosphoproteomic coverage through sequential digestion by complementary proteases. Analytical and bioanalytical chemistry. 2012; 402(2):711–20.
109. Nuhse TS, Bottrill AR, Jones AM, Peck SC. Quantitative phosphoproteomic analysis of plasma membrane proteins reveals regulatory mechanisms of plant innate immune responses. Plant J. 2007; 51 (5):931–40.
110. Nuhse TS, Stensballe A, Jensen ON, Peck SC. Large-scale analysis of in vivo phosphorylated membrane proteins by immobilized metal ion affinity chromatography and mass spectrometry. Molecular & cellular proteomics: MCP. 2003; 2(11):1234–43.
111. Blacken GR, Volny M, Vaisar T, Sadilek M, Turecek F. In situ enrichment of phosphopeptides onchemistry. 2007; 79(14):5449–56.
112. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 2006;127(3):635–48.
113. Boersema PJ, Foong LY, Ding VM, Lemeer S, van Breukelen B, Philp R, et al. In-depth qualitative and quantitative profiling of tyrosine phosphorylation using a combination of phosphopeptide immunoaffinity purification and stable isotope dimethyl labeling. Molecular & cellular proteomics: MCP. 2010; 9(1):84– 99.
114. Leibovitz A, Stinson JC, McCombs WB 3rd, McCoy CE, Mazur KC, Mabry ND. Classification of human colorectal adenocarcinoma cell lines. Cancer Res. 1976; 36(12):4562–9.
115. Peng-ChanLin, Yi-FangYang,Yu-ChangTyan,EricS.L.Hsiao,Po-ChenChu, Chung-TaLee, Jenq-ChangLee, Yi-MingArthur Chen, Pao-ChiLiao. Identification of Phosphorylated Cyclin Dependent Kinase1Associated with Colorectal Cancer Survival Using Label-Free Quantitative Analyses. PLOS one| DOI:10.1371/ journal. pone.0158844 July6, 2016.
116. Chiu KH, Chang YH, Wu YS, Lee SH, Liao PC. Quantitative secretome analysis reveals that COL6A1 is a metastasis-associated protein using stacking gel-aided purification combined with iTRAQ labeling. J Proteome Res. 2011; 10(3):1110–25.
117. Bellew M, Coram M, Fitzgibbon M, Igra M, Randolph T, Wang P, et al. A suite of algorithms for the comprehensive analysis of complex protein mixtures using high-resolution LC-MS. Bioinformatics. 2006; 22 (15):1902–9.
118. Yang T-H, Chang H-T, Hsiao E, Sun J-L, Wang C-C, Wu H-Y, et al. iPhos: a toolkit to streamline the alkaline phosphatase-assisted comprehensive LC-MS phosphoproteome investigation. BMC Bioinformatics. 2014; 15(Suppl 16):S10.
119. Yang TH, Chang HT, Hsiao ES, Sun JL, Wang CC, Wu HY, et al. iPhos: a toolkit to streamline the alkaline phosphatase-assisted comprehensive LC-MS phosphoproteome investigation. BMC Bioinformatics. 2014; 15 Suppl 16:S10.
120. Wang MC, Lee YH, Liao PC. Optimization of titanium dioxide and immunoaffinity-based enrichment procedures for tyrosine phosphopeptide using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Analytical and bioanalytical chemistry. 2015; 407(5):1343–56.
121. Marcantonio M, Trost M, Courcelles M, Desjardins M, Thibault P. Combined enzymatic and data mining approaches for comprehensive phosphoproteome analyses: application to cell signaling events of interferon-gamma-stimulated macrophages. Molecular & cellular proteomics: MCP. 2008; 7(4):645–60.
122. Imanishi SY, Kochin V, Ferraris SE, de Thonel A, Pallari HM, Corthals GL, et al. Reference-facilitated phosphoproteomics—Fast and reliable phosphopeptide validation by microLC-ESI-Q-TOF MS/MS. Molecular & Cellular Proteomics. 2007; 6(8):1380–91.
123. Marcantonio M, Trost M, Courcelles M, Desjardins M, Thibault P. Combined enzymatic and data mining approaches for comprehensive phosphoproteome analyses. Molecular & Cellular Proteomics. 2008; 7 (4):645–60.
124. Hornbeck PV, Chabra I, Kornhauser JM, Skrzypek E, Zhang B. PhosphoSite: A bioinformatics resource dedicated to physiological protein phosphorylation. Proteomics. 2004; 4(6):1551–61.
125. Gnad F, Ren S, Cox J, Olsen JV, Macek B, Oroshi M, et al. PHOSIDA (phosphorylation site database):management, structural and evolutionary investigation, and prediction of phosphosites. Genome Biol.2007; 8(11):R250.
126. Gnad F, Gunawardena J, Mann M. PHOSIDA 2011: the posttranslational modification database.Nucleic Acids Res. 2011; 39(Database issue):D253–60.
127. Sugiyama N, Masuda T, Shinoda K, Nakamura A, Tomita M, Ishihama Y. Phosphopeptide enrichment by aliphatic hydroxy acid-modified metal oxide chromatography for nano-LC-MS/MS in proteomics applications. Molecular & cellular proteomics: MCP. 2007; 6(6):1103–9.
128. Savitski MM, Lemeer S, Boesche M, Lang M, Mathieson T, Bantscheff M, et al. Confident phosphorylation site localization using the Mascot Delta Score. Molecular & cellular proteomics: MCP. 2011; 10(2):M110 003830.
129. Phipps AI, Buchanan DD, Makar KW, Win AK, Baron JA, Lindor NM, et al. KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers. Br J Cancer. 2013; 108(8):1757–64.
130. Moertel CG, O'Fallon JR, Go VL, O'Connell MJ, Thynne GS. The preoperative carcinoembryonic antigen test in the diagnosis, staging, and prognosis of colorectal cancer. Cancer. 1986; 58(3):603–10.
131. Fauzee NJ, Li Q, Wang YL, Pan J. Silencing Poly (ADP-Ribose) glycohydrolase (PARG) expression inhibits growth of human colon cancer cells in vitro via PI3K/Akt/NFkappa-B pathway. Pathol Oncol Res. 2012; 18(2):191–9.
132. Bianco C, Strizzi L, Mancino M, Rehman A, Hamada S, Watanabe K, et al. Identification of cripto-1 as a novel serologic marker for breast and colon cancer. Clin Cancer Res. 2006; 12(17):5158–64.
133. Henriksson ML, Edin S, Dahlin AM, Oldenborg PA, Oberg A, Van Guelpen B, et al. Colorectal cancer cells activate adjacent fibroblasts resulting in FGF1/FGFR3 signaling and increased invasion. Am J Pathol. 2011; 178(3):1387–94.
134. BaRAScu A, Besson P, Le Floch O, Bougnoux P, Jourdan ML. CDK1-cyclin B1 mediates the inhibition of proliferation induced by omega-3 fatty acids in MDA-MB-231 breast cancer cells. Int J Biochem Cell Biol. 2006; 38(2):196–208.
135. Zeestraten EC, Maak M, Shibayama M, Schuster T, Nitsche U, Matsushima T, et al. Specific activity of cyclin-dependent kinase I is a new potential predictor of tumour recurrence in stage II colon cancer. Br J Cancer. 2012; 106(1):133–40.
136. Castedo M, Perfettini JL, Roumier T, Kroemer G. Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ. 2002; 9(12):1287–93.
137. Potapova TA, Daum JR, Byrd KS, Gorbsky GJ. Fine tuning the cell cycle: activation of the Cdk1 inhibitory phosphorylation pathway during mitotic exit. Mol Biol Cell. 2009; 20(6):1737–48.
138. Welburn JP, Tucker JA, Johnson T, Lindert L, Morgan M, Willis A, et al. How tyrosine 15 phosphorylation inhibits the activity of cyclin-dependent kinase 2-cyclin A. J Biol Chem. 2007; 282(5):3173–81.
139. Smits VA, Medema RH. Checking out the G(2)/M transition. Biochim Biophys Acta. 2001; 1519(1–2):1– 12.
140. Boutros R, Lobjois V, Ducommun B. CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer. 2007; 7(7):495–507.
141. Parker LL, Piwnica-Worms H. Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science. 1992; 257(5078):1955–7.
142. Heald R, McLoughlin M, McKeon F. Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase. Cell. 1993; 74(3):463–74.
143. Squire CJ, Dickson JM, Ivanovic I, Baker EN. Structure and inhibition of the human cell cycle checkpoint kinase, Wee1A kinase: an atypical tyrosine kinase with a key role in CDK1 regulation. Structure. 2005; 13(4):541–50.
144. De Witt Hamer PC, Mir SE, Noske D, Van Noorden CJ, Wurdinger T. WEE1 kinase targeting combined with DNA-damaging cancer therapy catalyzes mitotic catastrophe. Clin Cancer Res. 2011; 17 (13):4200–7.
145. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. The New England journal of medicine. 2005; 353(2):172–87.
146. McGowan CH, Russell P. Cell cycle regulation of human WEE1. EMBO J. 1995; 14(10):2166–75.
147. Watanabe N, Broome M, Hunter T. Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J. 1995; 14(9):1878–91.
148. O'Connell MJ, Raleigh JM, Verkade HM, Nurse P. Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. EMBO J. 1997; 16(3):545–54.
149. Katayama K, Fujita N, Tsuruo T. Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol Cell Biol. 2005; 25(13):5725–37.
150. Mir SE, De Witt Hamer PC, Krawczyk PM, Balaj L, Claes A, Niers JM, et al. In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer cell. 2010; 18(3):244–57.
151. Hashimoto O, Ueno T, Kimura R, Ohtsubo M, Nakamura T, Koga H, et al. Inhibition of proteasomedependent degradation of Wee1 in G2-arrested Hep3B cells by TGF beta 1. Mol Carcinog. 2003; 36 (4):171–82.
152. Li J, Wang Y, Sun Y, Lawrence TS. Wild-type TP53 inhibits G(2)-phase checkpoint abrogation and radiosensitization induced by PD0166285, a WEE1 kinase inhibitor. Radiat Res. 2002; 157(3):322–30.
153. Wang Y, Li J, Booher RN, Kraker A, Lawrence T, Leopold WR, et al. Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint abrogator. Cancer Res. 2001; 61(22):8211–7.
154. Sung WW, Lin YM, Wu PR, Yen HH, Lai HW, Su TC, et al. High nuclear/cytoplasmic ratio of Cdk1 expression predicts poor prognosis in colorectal cancer patients. BMC Cancer. 2014; 14:951.
155. Hasegawa H, Nomura T, Kishimoto K, Yanagisawa K, Fujita S. SFA-1/PETA-3 (CD151), a member of the transmembrane 4 superfamily, associates preferentially with alpha 5 beta 1 integrin and regulates adhesion of human T cell leukemia virus type 1-infected T cells to fibronectin. J.Immunol. 1998;161:3087-3095.
156. Yanez-Mo M, Alfranca A, Cabanas C et al. Regulation of endothelial cell motility by complexes of tetraspanin molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions. J.Cell Biol. 1998;141:791-804.
157. Takeda Y, Kazarov AR, Butterfield CE et al. Deletion of tetraspaninin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro. Blood 2007;109:1524-1532.
158. Sterk LM, Geuijen CA, Oomen LC et al. The tetraspanin molecule CD151, a novel constituent of hemidesmosomes, associates with the integrin alpha6beta4 and may regulate the spatial organization of hemidesmosomes. J.Cell Biol. 2000;149:969-982.
159. Hashida H, Takabayashi A, Tokuhara T et al. Clinical significance of transmembrane 4 superfamily in colon cancer. Br.J.Cancer 2003;89:158-167.
160. Tokuhara T, Hasegawa H, Hattori N et al. Clinical significance of CD151 gene expression in non-small cell lung cancer. Clin.Cancer Res. 2001;7:4109-4114.
161. Ang J, Lijovic M, Ashman LK, Kan K, Frauman AG. CD151 protein expression predicts the clinical outcome of low-grade primary prostate cancer better than histologic grading: a new prognostic indicator? Cancer Epidemiol.Biomarkers Prev. 2004;13:1717-1721.
162. Chien CW, Lin SC, Lai YY et al. Regulation of CD151 by hypoxia controls cell adhesion and metastasis in colorectal cancer. Clin.Cancer Res. 2008;14:8043-8051.
163. Garcia-Lopez MA, Barreiro O, Garcia-Diez A, Sanchez-Madrid F, Penas PF. Role of tetraspaninins CD9 and CD151 in primary melanocyte motility. J.Invest Dermatol. 2005;125:1001-1009.
164. Peng-Chan Lin, Shao-Chieh Lin, Chung-Ta Lee, Yih-Jyh Lin, Jenq-Chang Lee.Dynamic Change of Tetraspanin CD151 Membrane Protein Expression in Colorectal Cancer Patients. Cancer Invest. 2011 Aug 30:
165. Winterwood NE, Varzavand A, Meland MN, Ashman LK, Stipp CS. A critical role for tetraspaninin CD151 in alpha3beta1 and alpha6beta4 integrin-dependent tumor cell functions on laminin-5. Mol.Biol.Cell 2006;17:2707-2721.
166. Hong IK, Jin YJ, Byun HJ et al. Homophilic interactions of Tetraspaninin CD151 up-regulate motility and matrix metalloproteinase-9 expression of human melanoma cells through adhesion-dependent c-Jun activation signaling pathways. J.Biol.Chem. 2006;281:24279-24292.
167. Yauch RL, Berditchevski F, Harler MB, Reichner J, Hemler ME. Highly stoichiometric, stable, and specific association of integrin alpha3beta1 with CD151 provides a major link to phosphatidylinositol 4-kinase, and may regulate cell migration. Mol.Biol.Cell 1998;9:2751-2765.
168. Zhang XA, Bontrager AL, Hemler ME. Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific beta(1) integrins. J.Biol.Chem. 2001;276:25005-25013.
169. Shigeta M, Sanzen N, Ozawa M et al. CD151 regulates epithelial cell-cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization. J.Cell Biol. 2003;163:165-176.
170. Chometon G, Zhang ZG, Rubinstein E et al. Dissociation of the complex between CD151 and laminin-binding integrins permits migration of epithelial cells. Exp.Cell Res. 2006;312:983-995.
171. Tabin CJ, Bradley SM, Bargmann CI, et al. Mechanism of activation of a human oncogene. Nature 1982;300:143-9.
172. Bruce WR, Wolever TM, Giacca A. Mechanisms linking diet and colorectal cancer: the possible role of insulin resistance. Nutr Cancer 2000;37:19-26.
173. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539-45.
174. Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer 2003;3:276-85.
175. Mariani F, Sena P, Marzona L, et al. Cyclooxygenase-2 and Hypoxia-Inducible Factor-1alpha protein expression is related to inflammation, and up-regulated since the early steps of colorectal carcinogenesis. Cancer Lett 2009;279:221-9.
176. Adegboyega PA, Ololade O, Saada J, Mifflin R, Di Mari JF, Powell DW. Subepithelial myofibroblasts express cyclooxygenase-2 in colorectal tubular adenomas. Clin Cancer Res 2004;10:5870-9.
177. Hawcroft G, Ko CW, Hull MA. Prostaglandin E2-EP4 receptor signalling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells. Oncogene 2007;26:3006-19.
178. Sun Y, Tang XM, Half E, Kuo MT, Sinicrope FA. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. Cancer Res 2002;62:6323-8.
179. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2001;2:612-9.
180. Charalambous MP, Lightfoot T, Speirs V, Horgan K, Gooderham NJ. Expression of COX-2, NF-kappaB-p65, NF-kappaB-p50 and IKKalpha in malignant and adjacent normal human colorectal tissue. Br J Cancer 2009;101:106-15.
181. Sano H, Kawahito Y, Wilder RL, et al. Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 1995;55:3785-9.
182. Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 1999;18:7908-16.
183. Zhang M, Deng CS, Zheng JJ, Xia J. Curcumin regulated shift from Th1 to Th2 in trinitrobenzene sulphonic acid-induced chronic colitis. Acta Pharmacol Sin 2006;27:1071-7.
184. Yamazaki K, Shimizu M, Okuno M, et al. Synergistic effects of RXR alpha and PPAR gamma ligands to inhibit growth in human colon cancer cells-phosphorylated RXR alpha is a critical target for colon cancer management. Gut 2007;56:1557-63.
185. Kitamura S, Miyazaki Y, Shinomura Y, Kondo S, Kanayama S, Matsuzawa Y. Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells. Jpn J Cancer Res 1999;90:75-80.
186. Kohno H, Suzuki R, Sugie S, Tanaka T. Suppression of colitis-related mouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands. BMC Cancer 2005;5:46.
187. Yuri M, Sasahira T, Nakai K, Ishimaru S, Ohmori H, Kuniyasu H. Reversal of expression of 15-lipoxygenase-1 to cyclooxygenase-2 is associated with development of colonic cancer. Histopathology 2007;51:520-7.
188. Sarraf P, Mueller E, Jones D, et al. Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med 1998;4:1046-52.
189. Peng-Chan Lin, YJ Lin, CT Lee, HS Liu and JC Lee. Cyclooxygenase 2 expression in the tumor environment is associated with poor prognosis in colorectal cancer patients. ONCOLOGY LETTERS 6: 733-739, 2013.
190. Tseng YS, Tzeng CC, Huang CY, et al. Aurora-A overexpression associates with Ha-RAS codon-12 mutation and blackfoot disease endemic area in bladder cancer. Cancer Lett 2006;241:93-101.
191. Cheng HL, Trink B, Tzai TS, et al. Overexpression of c-met as a prognostic indicator for transitional cell carcinoma of the urinary bladder: a comparison with p53 nuclear accumulation. J Clin Oncol 2002;20:1544-50.
192. Cutler NS, Graves-Deal R, LaFleur BJ, et al. Stromal production of prostacyclin confers an antiapoptotic effect to colonic epithelial cells. Cancer Res 2003;63:1748-51.
193. Karnes WE, Jr., Shattuck-Brandt R, Burgart LJ, et al. Reduced COX-2 protein in colorectal cancer with defective mismatch repair. Cancer Res 1998;58:5473-7.
194. Zuo X, Wu Y, Morris JS, et al. Oxidative metabolism of linoleic acid modulates PPAR-ΓΓbeta/delta suppression of PPAR gamma activity. Oncogene 2006;25:1225-41.
195. DuBois RN, Gupta R, Brockman J, Reddy BS, Krakow SL, Lazar MA. The nuclear eicosanoid receptor, PPAR gamma, is aberrantly expressed in colonic cancers. Carcinogenesis 1998;19:49-53.
196. Vandoros GP, Konstantinopoulos PA, Sotiropoulou-Bonikou G, et al. PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas. J Cancer Res Clin Oncol 2006;132:76-84.
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