蛋白質磷酸酶2A型(PP2A)為一種絲氨酸/蘇胺酸磷酸水解酶，已知具有抑癌的功能。而PP2A組成是由負責催化功能的C次單元、構成結構骨架的A次單元以及種類多樣的調節性B次單元，其中B次單元可決定PP2A完全酶的受質特異性以及其在細胞中座落的位置。而PP2A-B56γ3調節次單元已被證實具有抑制腫瘤生成的功能；然而，近年來亦有文獻指出B56γ3在某些癌症中都有過度表現的情形，但是目前對於B56γ3次單元在腫瘤轉移過程中所扮演的角色仍然是未知的。大腸癌是全世界常見且致命的癌症之一。我們實驗室之前分析大腸癌組織切片發現B56γ的表現與大腸癌的分期具有正相關性；另外，我們也從數據庫資料搜尋，發現相較於非腫瘤部位，在腫瘤部位中的B56γ3有較高的表現。綜合上述，我們推測B56γ3可能扮演著促進大腸癌轉移的角色。首先，我們分析了B56γ3在各種不同大腸癌細胞株(如: CT26, HCT116, HT29, DLD-1, CX-1及LS-147T)中的表現，由結果發現，在所有的大腸癌細胞中以HCT116細胞表現有最高的B56γ3，而HT29細胞中的B56γ3表現較低，因此，在後續實驗中我們主要以HCT116以及HT29細胞作為研究對象，來分析B56γ3是否會參與在調控大腸癌的轉移。我們發現B56γ3會抑制HCT116和HT29細胞的增殖。另外，先前研究已證實PI3K/AKT/mTOR訊息軸線能夠促進腫瘤的轉移，而我們發現到相較於HT29細胞而言，HCT116細胞中p70S6K在蘇胺酸389的磷酸化(mTOR活性的指標)以及其下游S6在絲氨酸235/236的磷酸化皆較高。另外，我們也建立過度表現B56γ3或以核糖核酸干擾法將B56γ3表現減低之細胞株，而從結果我們發現到在HCT116細胞中，B56γ3會抑制p70S6K在蘇胺酸389的磷酸化以及S6在絲氨酸235/236的磷酸化，卻會增加Akt在絲氨酸473及蘇胺酸308的磷酸化；而在HT29細胞中，B56γ3也會降低p70S6K在蘇胺酸389與S6在絲氨酸235/236的磷酸化，但Akt在絲氨酸473和蘇胺酸308的磷酸化卻受到抑制。接著，我們也觀察了上皮-間質細胞轉換(epithelial-mesenchymal transition, EMT)的標記分子表現是否也會受到B56γ3的調控。由實驗結果我們發現相較於HT29細胞而言，在HCT116細胞中E-cadherin, Twist以及Ep-CAM皆有較低的表現；然而vimentin與fibronectin的表現在這兩株細胞中則沒有差異。另外，我們也發現到B56γ3對於HCT116及HT29細胞中EMT marker的調控有相似或差異之處，其中B56γ3會抑制HT29細胞中Twist(EMT過程中的重要轉錄因子)，但此調控卻不在HCT116細胞中被發現。另外，在HT29細胞中，B56γ3可提高Ep-CAM表現，但在HCT116細胞中對Ep-CAM表現則異常失控。最後，我們藉由細胞的傷痕癒合運動能力(wound-healing migration assay)的實驗發現相較於HT29細胞而言，HCT116細胞有較高的運動能力。另一方面我們更是發現到B56γ3會促進HCT116細胞的運動能力，然而B56γ3卻是會抑制HT29細胞的運動能力。綜合以上結果，我們發現B56γ3能夠抑制p70S6K在蘇胺酸389的磷酸化及大腸癌細胞HCT116與HT29細胞的增殖能力，但對於Akt的磷酸化則是相反的調節角色，而在細胞運動能力、轉移相關的訊息軸線及EMT的標記分子表現的調控會因細胞的不同而有所差異。

The Ser/Thr protein phosphatase 2A (PP2A) has been recognized as a tumor suppressor. A PP2A holoenzyme is composed of a catalytic subunit (C), a structural subunit (A), and a highly variable regulatory subunit (B), which confers PP2A with diverse substrate specificity and subcellular localizations. The B56γ3-containing protein phosphatase 2A (PP2A-B56γ3) has been shown to inhibit tumorigenesis. However, a few studies have shown that B56γ3 was overexpressed in some cancer types. Importantly, the role of B56γ3 in tumor metastasis still remains unknown. Colorectal cancer (CRC) is a common and lethal disease worldwide. We have recently found that B56γ expression is positively correlated with advanced stages of CRC. Besides, our result of database mining showed that higher expression of B56γ3 in tumor parts was found in a CRC dataset as compared to non-tumor parts. We hypothesized that B56γ3 may promote CRC metastasis. We found that the protein expression levels of B56γ3 varied among several colon cancer cell lines, including CT26, HCT116, HT29, DLD-1, CX-1, and LS-147T cells. Among these, HCT116 cells showed the highest expression level of B56γ3. We investigated the role of B56γ3 in regulating characteristics of metastasis of HCT116 cells, and as a comparison, HT29, which showed lower levels of B56γ3 than that of HCT116, was also investigated. B56γ3 inhibits proliferation of both HCT116 and HT29 cells. The PI3K/AKT/mTOR signaling has been shown to promote metastasis. We found that the expression levels of both p70S6K and p70S6K phosphorylation at Thr389, an indicator for mTOR activity, and S6 phosphorylation at Ser235/235, the downstream target of p70S6K, were significantly higher in HCT116 cells as compared to that of HT29 cells. Furthermore, we established cells with stable overexpression or knockdown of B56γ3, and we found that B56γ3 negatively regulates Thr389 phosphorylation of p70S6K, and phosphorylation at Ser235/236 of S6, but increased Akt phosphorylation at Ser473 and Thr308, indicators of AKT activity, in HCT116 cells. Although B56γ3 similarly reduced Thr389 phosphorylation of p70S6K and Ser235/236 phosphorylation of S6 in HT29 cells, it decreased AKT phosphorylation at Ser473 and Thr308 in HT29 cells. Next, we examined protein levels of markers of epithelial-mesenchymal transition (EMT), and we found that the expression levels of E-cadherin, Twist and Ep-CAM were significantly lower in HCT116 cells as compared to that of HT29 cells. However, the levels of vimentin and fibronectin were not significantly altered in both HCT116 and HT29 cells. In addition, we found that B56γ3 acts similarly or differently in regulating expression of EMT markers in HCT116 and HT29 cells. The expression of Twist, a key EMT transcriptional factor, is negatively regulated by B56γ3 in HT29 cells, but is both negatively and positively regulated by B56γ3 in HCT116 cells. Finally, we assessed the motility of both HCT116 and HT29 cells. The motility of HCT116 cells was superior to that of HT29 cells. B56γ3 promotes motility of HCT116 cells, whereas it inhibits the motility of HT29 cells. In summary, B56γ3 inhibits proliferation of CRC HCT116 and HT29 cells, but oppositely regulates AKT activation, and differentially regulates motility, metastasis signaling and expression of EMT markers of CRC cells in a context-dependent manner.

1. Schlüter K, Gassmann P, Enns A, Korb T, Hemping-Bovenkerk A, Hölzen J, Haier J. Organ-specific metastatic tumor cell adhesion and extravasation of colon carcinoma cells with different metastatic potential. Am J Pathol. 2006; 169: 1064-73.
2. Tannaz Armaghany, Jon D. Wilson, Quyen Chu, Glenn Mills. Genetic Alterations in Colorectal Cancer. Gastrointest Cancer Res. 2012; 5: 19-27.
3. Polakis P. The adenomatous polyposis coli (APC) tumor suppressor. Biochim Biophys Acta. 1997; 1332: F127-47.
4. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996; 87: 159-70.
5. Lane DP, Benchimol S. p53: oncogene or anti-oncogene? Genes Dev. 1990; 4: 1-8.
6. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988; 319: 525-32.
7. Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med. 2011; 135: 1269-77.
8. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006; 38: 787-93.
9. Ogino S, Kawasaki T, Kirkner GJ, Suemoto Y, Meyerhardt JA, Fuchs CS. Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer. Gut. 2007; 56: 1564-71.
10. Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, Hernandez NS, Chen X, Ahmed S, Konishi K, Hamilton SR, Issa JP. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A. 2007; 104: 18654-9.
11. Jaya Sangodkar, Caroline Farrington, Kimberly McClinch, Matthew D. Galsky, David B. Kastrinsky, and Goutham Narla. All roads lead to PP2A: Exploiting the therapeutic potential of this phosphatase. FEBS J. 2016; 283: 1004-24.
12. Godfrey GrechEmail, Shawn Baldacchino, Christian Saliba, Maria Pia Grixti, Robert Gauci, Vanessa Petroni, Anthony G. Fenech, Christian Scerri. Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options. Tumor Biology. 2016; 37: 11691-11700.
13. Mumby, M. C., and G. Walter. Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth. Physiol. Rev. 1993; 73: 673-699.
14. Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD, Shi Y. Structure of the protein phosphatase 2A holoenzyme. Cell. 2006; 127: 1239-51.
15. Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J. 2001; 353: 417-39.
16. Lechward K, Awotunde OS, Swiatek W, Muszyńska G. Protein phosphatase 2A: variety of forms and diversity of functions. Acta Biochim Pol. 2001; 48: 921-33.
17. Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta. 2009; 1795: 1-15.
18. Groves MR, Hanlon N, Turowski P, Hemmings BA, Barford D. The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell. 1999; 96: 99-110.
19. Stefan Strack, Ralf Ruediger, Gernot Walter, Ruben K. Dagda, Chris A. Barwacz and J. Thomas Cribbs. Protein phosphatase 2A holoenzyme assembly: identification of contacts between B-family regulatory and scaffolding A subunits. J Biol Chem. 2002; 277: 20750-5.
20. R Ruediger, M Hentz, J Fait, M Mumby and G Walter. Molecular model of the A subunit of protein phosphatase 2A: interaction with other subunits and tumor antigens. J. Virol. 1994; 68: 123-129.
21. R Ruediger, D Roeckel, J Fait, A Bergqvist, G Magnusson and G Walter. Identification of binding sites on the regulatory A subunit of protein phosphatase 2A for the catalytic C subunit and for tumor antigens of simian virus 40 and polyomavirus. Mol Cell Biol. 1992; 12: 4872-4882.
22. Di Como CJ, Arndt KT. Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev. 1996; 10: 1904-1916.
23. Arino J, Woon CW, Brautigan DL, Miller TB Jr., Johnson GL.. Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes. Proc Natl Acad Sci U S A. 1988; 85: 4252-6
24. Khew-Goodall, Y. and Hemmings, B. A. Tissue-specific expression of mRNAs encoding a - and b -catalytic subunits of protein phosphatase 2A. FEBS Lett. 1988; 238: 265-268.
25. C. Van Hoof, J. Goris. Phosphatases in apoptosis: to be or not to be, PP2A is in the heart of the question. Biochim. Biophys. Acta. 2003; 1640: 97-104.
26. A.H. Schonthal Role of serine/threonine protein phosphatase 2A in cancer Cancer Lett. 2001; 170: 1-13.
27. Dagda RK, Zaucha JA, Wadzinski BE, Strack S. A developmentally regulated, neuron-specific splice variant of the variable subunit Bbeta targets protein phosphatase 2A to mitochondria and modulates apoptosis. J Biol Chem. 2003; 278: 24976-24985.
28. Strack S, Zaucha JA, Ebner FF, Colbran RJ, Wadzinski BE. Brain protein phosphatase 2A: developmental regulation and distinct cellular and subcellular localization by B subunits. J Comp Neurol. 1998; 392: 515-527.
29. Kuo YC, Huang KY, Yang CH, Yang YS, Lee WY, Chiang CW. Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt. J Biol Chem. 2008; 283: 1882-92.
30. McCright B, Rivers AM, Audlin S, Virshup DM. The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm. J Biol Chem. 1996; 271: 22081-22089.
31. Arnold HK, Sears RC. Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol. 2006; 26: 2832-44.
32. Li HH, Cai X, Shouse GP, Piluso LG, Liu X. A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO J. 2007; 26: 402-11.
33. Tehrani, M.A., Mumby, M. C. & Kamibayashi, C. Identification of a novel protein phosphatase 2A regulatory subunit highly expressed in muscle. J Biol Chem. 1996; 271: 5164-5170.
34. Muneer, S., et al. Genomic organization and mapping of the gene encoding the PP2A B56gamma regulatory subunit. Genomics. 2002; 79: 344-348.
35. Prajakta Varadkar, Daryl Despres, Matthew Kraman, Julie Lozier, Aditi Phadke, Kanneboyina Nagaraju, and Brent Mccright. The Protein Phosphatase 2A B56g Regulatory Subunit is Required for Heart Development. DEVELOPMENTAL DYNAMICS. 2014; 243: 778-90.
36. C. Bialojan, A. Takai, Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases, Specificity kinetics Biochem. J. 1988; 256: 283-290.
37. M. Suganuma, H. Fujiki, H. Suguri, S. Yoshizawa, M. Hirota, M. Nakayasu, M. Ojika, K. Wakamatsu, K. Yamada, T. Sugimura, Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter, Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 1768-1771.
38. M. Suganuma, H. Fujiki, H. Furuya-Suguri, S. Yoshizawa, S. Yasumoto, Y. Kato, N. Fusetani, T. Sugimura, Calyculin A, an inhibitor of protein phosphatases, a potent tumor promoter on CD-1 mouse skin, Cancer Res. 1990; 50: 3521-3525.
39. H. Fujiki, M. Suganuma, Tumor promotion by inhibitors of protein phosphatases 1 and 2A: the okadaic acid class of compounds, Adv. Cancer Res. 1992; 61: 143-194.
40. D.C. Pallas, L.K. Shahrik, B.L. Martin, S. Jaspers, T.B. Miller, D.L. Brautigan, T.M. Roberts, Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A, Cell. 1990; 60: 167-176.
41. R. Shtrichman, R. Sharf, H. Barr, T. Dobner, T. Kleinberger, Induction of apoptosis by adenovirus E4orf4 protein is specific to transformed cells and requires an interaction with protein phosphatase 2A, Proc. Natl. Acad. Sci. U. S A. 1999; 96: 10080-10085.
42. X. Cayla, K. Ballmer-Hofer, W. Merlevede, J. Goris, Phosphatase 2A associated with polyomavirus small-T or middle-T antigen is an okadaic acid-sensitive tyrosyl phosphatase, Eur. J. Biochem. 1993; 214: 281-286.
43. C. Kamibayashi, R. Estes, R.L. Lickteig, S.I. Yang, C. Craft, M.C. Mumby, Comparison of heterotrimeric protein phosphatase 2A containing different B subunits, J. Biol. Chem. 1994; 269: 20139-20148.
44. S.I. Yang, R.L. Lickteig, R. Estes, K. Rundell, G. Walter, M.C. Mumby, Control of protein phosphatase 2A by simian virus 40 small-t antigen, Mol. Cell Biol. 1991; 11: 1988-1995.
45. A. Ito, T.R. Kataoka, M. Watanabe, K. Nishiyama, Y. Mazaki, H. Sabe, Y. Kitamura, H. Nojima, A truncated isoform of the PP2A B56 subunit promotes cell motility through paxillin phosphorylation, EMBO. J. 2000; 19: 562-571.
46. Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC and Hahn WC. Identifi cation of specifi c PP2A complexes involved in human cell transformation. Cancer Cell. 2004; 5: 127-136.
47. Deichmann M, Polychronidis M, Wacker J, Thome M and Naher H. The protein phosphatase 2A subunit Bgamma gene is identifi ed to be differentially expressed in malignant melanomas by subtractive suppression hybridization. Melanoma Res. 2001; 11: 577-585.
48. Lee TY, Lai TY, Lin SC, Wu CW, Ni IF, Yang YS, Hung LY, Law BK, Chiang CW. The B56gamma3 regulatory subunit of protein phosphatase 2A (PP2A) regulates S phase-specific nuclear accumulation of PP2A and the G1 to S transition. J Biol Chem. 2010; 285: 21567-80.
49. Tai-Yu Lai, Chia-Jui Yen, Hung-Wen Tsai, Yu-San Yang, Wei-Fu Hong, Chi-Wu Chiang. The B56γ3 regulatory subunit-containing protein phosphatase 2A outcompetes Akt to regulate p27KIP1 subcellular localization by selectively dephosphorylating phospho-Thr157 of p27KIP1. Oncotarget. 2015; 7: 4542-58.
50. Haitao Zheng, Yu Chen, Shaohua Chen, Yuzhe Niu, Lijian Yang, Bo Li, Yuhong Lu, Suxia Geng, Xin Du, angqiu Li. Expression and distribution of PPP2R5C gene n leukemia. Journal of Hematology & Oncology. 2011; 4: 21-27.
51. Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. 2012; 2: 401-404.
52. Shin G, Kang TW, Yang S, Baek SJ, Jeong YS, Kim SY. GENT: gene expression database of normal and tumor tissues. Cancer Inform. 2011; 10: 149-57.
53. Szasz AM, Lanczky A, Nagy A, Forster S, Hark K, Green JE, Boussioutas A, Busuttil R, Szabo A, Gyorffy B. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget. 2016; 7: 49322-49333.
54. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997; 7: 261-9.
55. Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000; 346: 561-76.
56. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307: 1098-101.
57. Dahia PL. PTEN, a unique tumor suppressor gene. Endocr Relat Cancer. 2000; 7: 115-29.
58. Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol. 2004; 15: 177-82.
59. Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res. 1999; 253: 210-29.
60. Plas DR, Thompson CB. Akt-dependent transformation: there is more to growth than just surviving. Oncogene. 2005; 24: 7435-42.
61. Cantley LC, Neel BG: New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA. 1999; 96: 4240-4245.
62. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002; 2: 489-501.
63. Alfonso Bellacosa, C. Chandra Kumar, Antonio Di Cristofano, Joseph Robert Testa. Activation of AKT Kinases in Cancer: Implications for Therapeutic Targeting. 2005; 94: 29-86.
64. Ji Luo, Brendan D Manning, Lewis C Cantley. Targeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell. 2003; 4: 257-262.
65. Mitsiades CS, Mitsiades N, Koutsilieris M. The Akt pathway: molecular targets for anti-cancer drug development. Curr Cancer Drug Targets. 2004; 4: 235-56.
66. Dufner A, Thomas G. Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res. 1999; 253: 100-9.
67. Isotani S, Hara K, Tokunaga C et al. Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro. J Biol Chem. 1999; 274: 34493-8.
68. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl Acad. Sci. USA 1998; 95: 1432-7.
69. Hahn K, Miranda M, Francis VA, Vendrell J, Zorzano A, Teleman AA. PP2A regulatory subunit PP2A-B' counteracts S6K phosphorylation. Cell Metab. 2010; 11: 438-44.
70. Filonenko VV, Tytarenko R, Azatjan SK, et al. Immunohistochemical analysis of S6K1 and S6K2 localization in human breast tumors. Exp Oncol. 2004; 26: 294-9.
71. Nozawa H, Watanabe T, Nagawa H. Phosphorylation of ribosomal p70 S6 kinase and rapamycin sensitivity in human colorectal cancer. Cancer Lett. 2007; 251: 105-13.
72. Sahin F, Kannangai R, Adegbola O, et al. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res. 2004; 10: 8421-5.
73. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006; 5: 671-88.
74. Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008; 68: 8022-30.
75. Sun SY, Rosenberg LM, Wang X, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005; 65: 7052-8.
76. O’Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006; 66: 1500-8.
77. Kalluri, R., and Neilson, E.G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 2003; 112: 1776-1784.
78. Raghu Kalluri, and Robert A. Weinberg. The basics of epithelial-mesenchymal transition.  J. Clin. Invest. 2009; 119: 1420-1428.
79. Punnya V. Angadi, Alka D. Kale. Epithelial‑mesenchymal transition ‑ A fundamental mechanism in cancer progression: An overview. Indian j health sci 2015; 8: 77-84.
80. Kang Ae Lee, and Celeste M. Nelson. New Insights into the Regulation of Epithelial–Mesenchymal Transition and Tissue Fibrosis. International Review of Cell and Molecular Biology. 2012; 294: 171-221.
81. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006; 7: 131-42.
82. Bernardina T.F.van der Gun, Lieuwe J.Melchers, Marcel H.J.Ruiters, Lou F.M.H.de Leij, Pamela M.J.McLaughlin and Marianne G.Rots. EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis. 2010; 31: 1913-1921.
83. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006; 6: 392-401.
84. Guarino M, Rubino B, Ballabio G. The role of epithelial‑mesenchymal transition in cancer pathology. Pathology 2007; 39: 305-18.
85. SD Webley, RJ Francis, RB Pedley, SK Sharma, RHJ Begent, JA Hartley and D Hochhauser. Measurement of the critical DNA lesions produced by antibody-directed enzyme prodrug therapy (ADEPT) in vitro, in vivo and in clinical material. British Journal of Cancer. 2001; 84: 1671-1676.
86. John C CastleEmail author, Martin Loewer, Sebastian Boegel, Jos de Graaf, Christian Bender, Arbel D Tadmor, Valesca Boisguerin, Thomas Bukur, Patrick Sorn, Claudia Paret, Mustafa Diken, Sebastian Kreiter, Özlem Türeci and Ugur Sahin. Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma. BMC Genomics. 2014; 15: 190-202.
87. Goldin, A., Venditti, J. M., Macdonald, J. S., Muggia, F. M., Henney, J. E., Devita, V. T., Jr.. Current results of the screening program at the Division of Cancer Treatment, National Cancer Institute. European journal of cancer. 1990; 17: 129-142 .
88. D Ahmed, P W Eide, I A Eilertsen, S A Danielsen, M Eknæs, M Hektoen, G E Lind and R A Lothe. Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis. 2013; 2: e71-79.
89. G.M. Howell, L.E. Humphrey, R.A. Awwad, et al. Aberrant regulation of transforming growth factor-alpha during the establishment of growth arrest and quiescence of growth factor independent cells. J Biol Chem. 1998; 273: 9214-23.
90. Ying Liu and Walter F. Bodmer. Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines. PNAS. 2006; 103: 976-981
91. P A J Muller, A G Trinidad, P Timpson, J P Morton, S Zanivan, P V E van den Berghe, C Nixon, S A Karim, P T Caswell, J E Noll, C R Coffill, D P Lane, O J Sansom, P M Neilsen, J C Norman, and K H Vousden. Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion. Oncogene. 2013; 32: 1252-1265.
92. Veerle Janssens, Jozef Goris and Christine Van Hoof. PP2A: the expected tumor suppressor. Current Opinion in Genetics & Development. 2005; 15: 34-41.
93. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Reviews Cancer. 2009; 9: 550-562.
94. Amancio Carnero, and imageJesus M. Paramio. The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Front Oncol. 2014; 4: 252-262.
95. Tasuku Matsuoka 1 and Masakazu Yashiro. The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma. Cancers. 2014; 6: 1441-1463.
96. Anice Moumen, Salvatore Patané, Almudena Porras, Rosanna Dono, Flavio Maina. Met acts on Mdm2 via mTOR to signal cell survival during development. Development. 2007; 134: 1443-145.
97. Brian Ell, Yibin Kang. Transcriptional control of cancer metastasis. Trends in Cell Biology. 2013; 23: 603-611.
98. Lionel Larue and Alfonso Bellacosa. Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3’ kinase/AKT pathways. Oncogene. 2005; 24: 7443-7454.
99. Louis-Andre Julien, Audrey Carriere, Julie Moreau, and Philippe P. Roux. mTORC1-Activated S6K1 Phosphorylates Rictor on Threonine 1135 and Regulates mTORC2 Signaling. MOLECULAR AND CELLULAR BIOLOGY. 2010; 30: 908-921.
100. Bernardina T.F.van der Gun, Lieuwe J.Melchers, Marcel H.J.Ruiters, Lou F.M.H.de Leij, Pamela M.J.McLaughlin and Marianne G.Rots. EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis. 2010: 31: 1913-1921.
101. Nadim Maghzal, Hulya A. Kayali, Nazanin Rohani, Andrey V. Kajava, and Francois Fagotto. EpCAM Controls Actomyosin Contractility and Cell Adhesion by Direct Inhibition of PKC. Developmental Cell. 2013; 27: 263-277.
102. Guo F, Parker Kerrigan BC, Yang D, Hu L, Shmulevich I, Sood AK, Xue F, Zhang W. Post-transcriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions. J Hematol Oncol. 2014; 7: 19-30.
103. Gongda Xue, Brian A. Hemmings. PKB/Akt–Dependent Regulation of Cell Motility. J Natl Cancer Inst. 2013; 105: 393-404.
104. Xuan Liu, Qing Ji, Zhongze Fan and Qi Li. Cellular signaling pathways implicated in metastasis of colorectal cancer and the associated targeted agents. Future Oncol. 2015; 11: 2911-22.
105. Parri M, Chiarugi P. Rac and Rho GTPases in cancer cell motility control. Cell Communication and Signaling. 2010; 8: 23-37.