STK4是絲胺酸／蘇胺酸激酶蛋白，可轉譯出487個胺基酸在Hippo訊息傳遞路徑調控發育中扮演重要的調控角色。現今已知和STK4表現下降相關的疾病為腫瘤的再復發及肝炎的形成。然而調控STK4蛋白質表現及調控機制尚未明瞭。為了回答STK4蛋白質在細胞內扮演何種功能，本篇使用了線蟲作為模式生物加以做進一步的探討。在cst-1不表現的組別中腸胃道的寬度較控制組別來得寬且有提早老化的現象。-catenin 的同源基因bar-1也參與腸胃道發育的調控機制中。bar-1表現量下降所造成的提早老化及腸胃道過寬的現象也可藉過度表現cst-1而被回復。STK4 蛋白質表現量的調控依然未明。其中有一項可能為調控蛋白質的生合成可能是藉由轉錄後調控藉由微小核糖核酸(miRAN)結合至信使核糖核酸(mRNA)的3端促使降解。在功能分析及臨床檢體中都顯示出miR-18a 是一個致癌的微小核糖核酸藉由抑制STK4的蛋白質表現後所誘使的細胞自嗜經由AKT的磷酸化調控。由於在線蟲的結果中知道beta-catenin可能為STK4相互作用的蛋白質進一步作用在同一條訊息傳遞路徑中以調控腸胃道的發育。以免疫染色方式偵測STK4的表現在不同種類的腫瘤部位的表現，發現在前列腺，肝臟及大腸部分的癌化部分的染色表現明顯較非癌化的部位表現低。本篇的結果指出STK4是為一個抑癌蛋白藉由和beta-catenin的相互結合而達到抑制癌症的效果在攝護腺及大腸直腸癌中。STK4蛋白質的調控是藉由微小核糖核酸進行調控。本研究證明STK4可能可作為一個治療的標靶在攝護腺及大腸直腸癌。

STK4 is a serine/threonine kinase protein encoded for 487 amino acids which plays an important role in Hippo pathway involved in development progression. Disease associated with STK4 down-regulation induces tumor recurrent and hepatocellular carcinoma formation. However, the regulation mechanism of protein expression and function are still not clear. To address the STK4 protein function in the creatures that model organism C.elegans were used to answer this question. The intestinal tract distance of cst-1 knock-out has wider than control group and premature aging has been shown. -catenin homologous bar-1 is also involved in intestinal tract development regulation mechanism. The premature aging and intestine abnormality can be restored under bar-1 down-regulated with cst-1 over-expressed. STK4 protein expression level regulation mechanism is still unknown. One possibility is post-transcriptional regulation through miRNA targeting mRNA 3’UTR degradation. The function assay and clinical samples showed that miR-18a indeed is an oncomiR to suppress STK4 induced apoptosis cascade through AKT phosphorylation regulation. Above the data from C. elegans,beta-catenin can be the candidate target interacted with STK4 in the same axis to regulate digestive tract development. IHC staining of different kinds of tumor parts showed that STK4 are highly expressed in prostate, liver and colon compared with normal specimens. All of our study indicated that STK4 is a tumor suppressor interacted with beta-catenin in prostate and colon cancers. The protein synthesis is through miRNA mediated degradation. The study demonstrated that STK4 can be the therapeutic target for prostate and colon cancer.

1 Creasy CL, Chernoff J. Cloning and characterization of a human protein kinase with homology to Ste20. J Biol Chem 1995; 270: 21695-21700.

2 Taylor LK, Wang HC, Erikson RL. Newly identified stress-responsive protein kinases, Krs-1 and Krs-2. Proc Natl Acad Sci U S A 1996; 93: 10099-10104.

3 Cinar B, Fang PK, Lutchman M, Di Vizio D, Adam RM, Pavlova N et al. The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1. EMBO J 2007; 26: 4523-4534.

4 Zhao B, Lei QY, Guan KL. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol 2008; 20: 638-646.

5 Harvey KF, Pfleger CM, Hariharan IK. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 2003; 114: 457-467.

6 Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer cell 2009; 16: 425-438.

7 Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci U S A 2010; 107: 1437-1442.

8 Creasy CL, Ambrose DM, Chernoff J. The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain. J Biol Chem 1996; 271: 21049-21053.

9 Graves JD, Draves KE, Gotoh Y, Krebs EG, Clark EA. Both phosphorylation and caspase-mediated cleavage contribute to regulation of the Ste20-like protein kinase Mst1 during CD95/Fas-induced apoptosis. J Biol Chem 2001; 276: 14909-14915.

10 Lee KK, Ohyama T, Yajima N, Tsubuki S, Yonehara S. MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J Biol Chem 2001; 276: 19276-19285.

11 Cheung WL, Ajiro K, Samejima K, Kloc M, Cheung P, Mizzen CA et al. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 2003; 113: 507-517.

12 Jang SW, Yang SJ, Srinivasan S, Ye K. Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. J Biol Chem 2007; 282: 30836-30844.

13 Ura S, Masuyama N, Graves JD, Gotoh Y. Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation. Proc Natl Acad Sci U S A 2001; 98: 10148-10153.

14 Oh S, Lee D, Kim T, Kim TS, Oh HJ, Hwang CY et al. Crucial role for Mst1 and Mst2 kinases in early embryonic development of the mouse. Mol Cell Biol 2009; 29: 6309-6320.

15 Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR et al. Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer. Mod Pathol 2007; 20: 331-338.

16 Seidel C, Schagdarsurengin U, Blumke K, Wurl P, Pfeifer GP, Hauptmann S et al. Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol Carcinog 2007; 46: 865-871.

17 Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci U S A 2010; 107: 1431-1436.

18 Qiao M, Wang Y, Xu X, Lu J, Dong Y, Tao W et al. Mst1 is an interacting protein that mediates PHLPPs' induced apoptosis. Molecular cell 2010; 38: 512-523.

19 Steinmann K, Sandner A, Schagdarsurengin U, Dammann R. Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. Oncology reports 2009; 22: 1519-1526.

20 Wu S, Huang J, Dong J, Pan D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 2003; 114: 445-456.

21 Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol 2003; 5: 914-920.

22 Zhou D, Zhang Y, Wu H, Barry E, Yin Y, Lawrence E et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc Natl Acad Sci U S A 2011; 108: 31.

23 Zou CG, Tu Q, Niu J, Ji XL, Zhang KQ. The DAF-16/FOXO transcription factor functions as a regulator of epidermal innate immunity. PLoS Pathog 2013; 9: 17.

24 Crawford ED. Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology 2009; 73: S4-10.

25 Shen R, Sumitomo M, Dai J, Harris A, Kaminetzky D, Gao M et al. Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase. Endocrinology 2000; 141: 1699-1704.

26 Wong WY, Chen SC, Chueh SC, Chen J. The trend of managing prostate cancer in Taiwan. Int J Urol 2004; 11: 510-514.

27 Michael A, Stephan C, Schnorr D, Loening SA, Jung K. Serum macrophage migration inhibitory factor is not elevated in patients with prostate cancer. Cancer Epidemiol Biomarkers Prev 2004; 13: 328-329.

28 Olsson AY, Cooper CS. The molecular basis of prostate cancer. Br J Hosp Med (Lond) 2005; 66: 612-616.

29 Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759-767.

30 Bostwick DG, Brawer MK. Prostatic intra-epithelial neoplasia and early invasion in prostate cancer. Cancer 1987; 59: 788-794.

31 Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993; 150: 379-385.

32 Dong JT. Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer Metastasis Rev 2001; 20: 173-193.

33 Sun J, Liu W, Adams TS, Li X, Turner AR, Chang B et al. DNA copy number alterations in prostate cancers: a combined analysis of published CGH studies. Prostate 2007; 67: 692-700.

34 Abate-Shen C, Shen MM. Molecular genetics of prostate cancer. Genes Dev 2000; 14: 2410-2434.

35 Karan D, Lin MF, Johansson SL, Batra SK. Current status of the molecular genetics of human prostatic adenocarcinomas. Int J Cancer 2003; 103: 285-293.

36 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: a cancer journal for clinicians 2010; 60: 277-300.

37 Liu LX, Zhang WH, Jiang HC. Current treatment for liver metastases from colorectal cancer. World journal of gastroenterology : WJG 2003; 9: 193-200.

38 Grundmann RT. Current state of surgical treatment of liver metastases from colorectal cancer. World journal of gastrointestinal surgery 2011; 3: 183-196.

39 Gillams AR, Lees WR. Five-year survival in 309 patients with colorectal liver metastases treated with radiofrequency ablation. European radiology 2009; 19: 1206-1213.

40 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. Annals of surgery 2002; 235: 759-766.

41 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. Annals of surgical oncology 2007; 14: 1151-1160.

42 Abdalla EK, Vauthey JN, Ellis LM, Ellis V, Pollock R, Broglio KR et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Annals of surgery 2004; 239: 818-825; discussion 825-817.

43 Medema JP. Cancer stem cells: the challenges ahead. Nature cell biology 2013; 15: 338-344.

44 Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell stem cell 2014; 14: 275-291.

45 Kaiser J. The cancer stem cell gamble. Science 2015; 347: 226-229.

46 Snippert HJ, van Es JH, van den Born M, Begthel H, Stange DE, Barker N et al. Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenterology 2009; 136: 2187-2194 e2181.

47 Zeilstra J, Joosten SP, Dokter M, Verwiel E, Spaargaren M, Pals ST. Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer research 2008; 68: 3655-3661.

48 Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nature reviews Cancer 2003; 3: 453-458.

49 Ito K, Bernardi R, Pandolfi PP. A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer-initiating cell. Current opinion in genetics & development 2009; 19: 51-59.

50 Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature reviews Cancer 2008; 8: 755-768.

51 Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 2011; 331: 1559-1564.

52 Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006; 127: 679-695.

53 Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. The New England journal of medicine 1986; 315: 1650-1659.

54 Doljanski F. The sculpturing role of fibroblast-like cells in morphogenesis. Perspectives in biology and medicine 2004; 47: 339-356.

55 Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. The Journal of clinical investigation 2003; 112: 1776-1784.

56 Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003; 15: 740-746.

57 Thiery JP. Cell adhesion in development: a complex signaling network. Current opinion in genetics & development 2003; 13: 365-371.

58 Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci U S A 2001; 98: 10356-10361.

59 Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117: 927-939.

60 Barth AI, Nathke IS, Nelson WJ. Cadherins, catenins and APC protein: interplay between cytoskeletal complexes and signaling pathways. Curr Opin Cell Biol 1997; 9: 683-690.

61 Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997; 275: 1787-1790.

62 Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 1997; 275: 1784-1787.

63 He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT et al. Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 1509-1512.

64 Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422-426.

65 Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14: 1837-1851.

66 Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 2003; 421: 268-272.

67 Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11-22.

68 Dogar AM, Towbin H, Hall J. Suppression of latent transforming growth factor (TGF)-beta1 restores growth inhibitory TGF-beta signaling through microRNAs. The Journal of biological chemistry 2011; 286: 16447-16458.

69 Li L, Shi JY, Zhu GQ, Shi B. MiR-17-92 cluster regulates cell proliferation and collagen synthesis by targeting TGFB pathway in mouse palatal mesenchymal cells. Journal of cellular biochemistry 2012; 113: 1235-1244.

70 Fox JL, Dews M, Minn AJ, Thomas-Tikhonenko A. Targeting of TGFbeta signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma. Rna 2013; 19: 177-190.

71 Zou CG, Tu Q, Niu J, Ji XL, Zhang KQ. The DAF-16/FOXO transcription factor functions as a regulator of epidermal innate immunity. PLoS Pathog 2013; 9: e1003660.

72 McGhee JD. The C. elegans intestine. WormBook : the online review of C elegans biology 2007: 1-36.

73 Herman M. C. elegans POP-1/TCF functions in a canonical Wnt pathway that controls cell migration and in a noncanonical Wnt pathway that controls cell polarity. Development 2001; 128: 581-590.

74 Segbert C, Johnson K, Theres C, van Furden D, Bossinger O. Molecular and functional analysis of apical junction formation in the gut epithelium of Caenorhabditis elegans. Developmental biology 2004; 266: 17-26.

75 Natarajan L, Witwer NE, Eisenmann DM. The divergent Caenorhabditis elegans beta-catenin proteins BAR-1, WRM-1 and HMP-2 make distinct protein interactions but retain functional redundancy in vivo. Genetics 2001; 159: 159-172.

76 Eisenmann DM, Maloof JN, Simske JS, Kenyon C, Kim SK. The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development. Development 1998; 125: 3667-3680.

77 Pan D. Hippo signaling in organ size control. Genes Dev 2007; 21: 886-897.

78 Clevers H. Wnt/β-Catenin Signaling in Development and Disease. Cell 2006; 127: 469-480.

79 Haegel H, Larue L, Ohsugi M, Fedorov L, Herrenknecht K, Kemler R. Lack of beta-catenin affects mouse development at gastrulation. Development 1995; 121: 3529-3537.

80 So S, Miyahara K, Ohshima Y. Control of body size in C. elegans dependent on food and insulin/IGF-1 signal. Genes Cells 2011; 16: 639-651.

81 McCulloch D, Gems D. Body size, insulin/IGF signaling and aging in the nematode Caenorhabditis elegans. Exp Gerontol 2003; 38: 129-136.

82 Guo J, Miao Y, Xiao B, Huan R, Jiang Z, Meng D et al. Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. Journal of gastroenterology and hepatology 2009; 24: 652-657.

83 Motoyama K, Inoue H, Takatsuno Y, Tanaka F, Mimori K, Uetake H et al. Over- and under-expressed microRNAs in human colorectal cancer. International journal of oncology 2009; 34: 1069-1075.

84 Yao Y, Suo AL, Li ZF, Liu LY, Tian T, Ni L et al. MicroRNA profiling of human gastric cancer. Mol Med Report 2009; 2: 963-970.

85 Zhang ZW, An Y, Teng CB. [The roles of miR-17-92 cluster in mammal development and tumorigenesis]. Yi chuan = Hereditas / Zhongguo yi chuan xue hui bian ji 2009; 31: 1094-1100.

86 Wang YX, Zhang XY, Zhang BF, Yang CQ, Chen XM, Gao HJ. Initial study of microRNA expression profiles of colonic cancer without lymph node metastasis. Journal of digestive diseases 2010; 11: 50-54.

87 Yeh SH, Chen PJ. Gender disparity of hepatocellular carcinoma: the roles of sex hormones. Oncology 2010; 78 Suppl 1: 172-179.

88 Alencar AJ, Malumbres R, Kozloski GA, Advani R, Talreja N, Chinichian S et al. MicroRNAs are independent predictors of outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. Clinical cancer research : an official journal of the American Association for Cancer Research 2011; 17: 4125-4135.

89 Brock M, Trenkmann M, Gay RE, Gay S, Speich R, Huber LC. MicroRNA-18a enhances the interleukin-6-mediated production of the acute-phase proteins fibrinogen and haptoglobin in human hepatocytes. The Journal of biological chemistry 2011; 286: 40142-40150.

90 Morimura R, Komatsu S, Ichikawa D, Takeshita H, Tsujiura M, Nagata H et al. Novel diagnostic value of circulating miR-18a in plasma of patients with pancreatic cancer. British journal of cancer 2011; 105: 1733-1740.

91 Yang Y, Ding L, An Y, Zhang ZW, Lang Y, Tai S et al. MiR-18a regulates expression of the pancreatic transcription factor Ptf1a in pancreatic progenitor and acinar cells. FEBS letters 2012; 586: 422-427.

92 Wu W, Takanashi M, Borjigin N, Ohno SI, Fujita K, Hoshino S et al. MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis. British journal of cancer 2013.

93 Yang X, Du WW, Li H, Liu F, Khorshidi A, Rutnam ZJ et al. Both mature miR-17-5p and passenger strand miR-17-3p target TIMP3 and induce prostate tumor growth and invasion. Nucleic acids research 2013; 41: 9688-9704.

94 Sikand K, Slane SD, Shukla GC. Intrinsic expression of host genes and intronic miRNAs in prostate carcinoma cells. Cancer cell international 2009; 9: 21.

95 Xu Y, Fang F, Zhang J, Josson S, St Clair WH, St Clair DK. miR-17* suppresses tumorigenicity of prostate cancer by inhibiting mitochondrial antioxidant enzymes. PloS one 2010; 5: e14356.

96 Kim K, Chadalapaka G, Pathi SS, Jin UH, Lee JS, Park YY et al. Induction of the transcriptional repressor ZBTB4 in prostate cancer cells by drug-induced targeting of microRNA-17-92/106b-25 clusters. Molecular cancer therapeutics 2012; 11: 1852-1862.

97 Sylvestre Y, De Guire V, Querido E, Mukhopadhyay UK, Bourdeau V, Major F et al. An E2F/miR-20a autoregulatory feedback loop. The Journal of biological chemistry 2007; 282: 2135-2143.

98 Reszka AA, Halasy-Nagy JM, Masarachia PJ, Rodan GA. Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. The Journal of biological chemistry 1999; 274: 34967-34973.

99 Liu WH, Yeh SH, Lu CC, Yu SL, Chen HY, Lin CY et al. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology 2009; 136: 683-693.

100 Vichalkovski A, Gresko E, Cornils H, Hergovich A, Schmitz D, Hemmings BA. NDR kinase is activated by RASSF1A/MST1 in response to Fas receptor stimulation and promotes apoptosis. Curr Biol 2008; 18: 1889-1895.

101 Avruch J, Praskova M, Ortiz-Vega S, Liu M, Zhang XF. Nore1 and RASSF1 regulation of cell proliferation and of the MST1/2 kinases. Methods Enzymol 2006; 407: 290-310.

102 Hergovich A, Hemmings BA. Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling. Biofactors 2009; 35: 338-345.

103 Zhang L, Yue T, Jiang J. Hippo signaling pathway and organ size control. Fly 2009; 3: 68-73.

104 Zhou D, Zhang Y, Wu H, Barry E, Yin Y, Lawrence E et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc Natl Acad Sci U S A 2011; 108: E1312-1320.

105 Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M et al. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J 1998; 17: 2224-2234.

106 Ura S, Masuyama N, Graves JD, Gotoh Y. MST1-JNK promotes apoptosis via caspase-dependent and independent pathways. Genes Cells 2001; 6: 519-530.

107 De Souza PM, Kankaanranta H, Michael A, Barnes PJ, Giembycz MA, Lindsay MA. Caspase-catalyzed cleavage and activation of Mst1 correlates with eosinophil but not neutrophil apoptosis. Blood 2002; 99: 3432-3438.

108 Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang X-f et al. Identification of a Novel Ras-Regulated Proapoptotic Pathway. Current Biology 2002; 12: 253-265.

109 de Souza PM, Lindsay MA. Mammalian Sterile20-like kinase 1 and the regulation of apoptosis. Biochem Soc Trans 2004; 32: 485-488.

110 Aoyama Y, Avruch J, Zhang XF. Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases. Oncogene 2004; 23: 3426-3433.

111 Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 2006; 125: 987-1001.

112 Oh HJ, Lee KK, Song SJ, Jin MS, Song MS, Lee JH et al. Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis. Cancer Res 2006; 66: 2562-2569.

113 Zhai XH, Yu JK, Yang FQ, Zheng S. Identification of a new protein biomarker for colorectal cancer diagnosis. Molecular medicine reports 2012; 6: 444-448.

114 Adams H, Tzankov A, Lugli A, Zlobec I. New time-dependent approach to analyse the prognostic significance of immunohistochemical biomarkers in colon cancer and diffuse large B-cell lymphoma. Journal of clinical pathology 2009; 62: 986-997.

115 Mou F, Praskova M, Xia F, Van Buren D, Hock H, Avruch J et al. The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. The Journal of experimental medicine 2012; 209: 741-759.