title: MACC1 Induces Tumor Progression in Transgenic Mice and Colorectal Cancer Patients via Increased Pluripotency Markers Nanog and Oct4.
abstract: We have previously identified the gene MACC1 as a strong prognostic biomarker for colorectal cancer metastasis and patient survival. Here, we report for the first time the generation of transgenic mouse models for MACC1.
  
  
  
  We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with Apc(Min) mice (vil-MACC1/Apc(Min)).
  
  
  
  vil-MACC1/Apc(Min) mice significantly increased the total number of tumors (P = 0.0056). This was particularly apparent in large tumors (≥3-mm diameter; P = 0.0024). A detailed histopathologic analysis of these lesions demonstrated that the tumors from the vil-MACC1/Apc(Min) mice had a more invasive phenotype and, consequently, showed a significantly reduced survival time than Apc(Min) mice (P = 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/Apc(Min) mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors compared with Apc(Min) controls. Finally, we could also validate that Oct4 and Nanog are regulated by MACC1 in vitro and strongly correlate with MACC1 levels in a cohort of 60 tumors of colorectal cancer patients (r = 0.7005 and r = 0.6808, respectively; P > 0.0001 and P > 0.0002, respectively).
  
  
  
  We provide proof of principle that MACC1-induced tumor progression in colorectal cancer acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis. These findings might have important implications for the design of novel therapeutic intervention strategies to restrict tumor progression. Clin Cancer Res; 22(11); 2812-24. ©2016 AACR.
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. lemosc@gmail.com ustein@mdc-berlin.de.
authors.forename: Clara
authors.initials: C
authors.lastname: Lemos
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. German Cancer Consortium, Heidelberg, Germany.
authors.forename: Markus S
authors.initials: MS
authors.lastname: Hardt
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Manisha
authors.initials: M
authors.lastname: Juneja
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. German Cancer Consortium, Heidelberg, Germany.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Voss
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Förster
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Jerchow
authors.affiliation: Institute for Animal Pathology, Berlin, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Haider
authors.affiliation: Institute of Pathology, Charité Medical Faculty, Berlin, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Bläker
authors.affiliation: Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. German Cancer Consortium, Heidelberg, Germany. lemosc@gmail.com ustein@mdc-berlin.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stein
mesh_terms: D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*; D060449:Wnt Signaling Pathway
chemical_list: C544162:MACC1 protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors