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Suppression of Intestinal Polyposis in Mdr1-Deficient Apcmin/ Mice1

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Suppression of Intestinal Polyposis in Mdr1-Deficient Apcmin/ Mice1 [CANCER RESEARCH 63, 895–901, March 1, 2003] Advances in Brief Suppression of Intestinal Polyposis in Mdr1-deficient ApcMin/؉ Mice1 Tesshi Yamada,2 Yasuharu Mori, Reiko Hayashi, Mizuho Takada, Yoshinori Ino, Yasuyoshi Naishiro, Tadashi Kondo, and Setsuo Hirohashi Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan Abstract functional involvement of the MDR1 gene in intestinal tumorigenesis. We report suppression of intestinal tumorigenesis in ApcMin/ϩ mice ␤ Aberrant transactivation of a certain set of target genes by the -catenin lacking functional Mdr1 genes. and T-cell factor/lymphoid enhancer factor complex has been considered crucial for the initiation of intestinal tumorigenesis. The human multidrug Materials and Methods resistance (MDR)1 (ABCB1) gene contains multiple ␤-catenin–T-cell factor4- binding elements in its promoter and is one of the immediate targets of the Antibodies, Immunoblot Analyses, Immunohistochemistry, and Immu- complex. In the current study, we have further substantiated the biological nofluorescence Microscopy. Anti-␤-catenin monoclonal antibody (clone 14) involvement of MDR1 in intestinal tumorigenesis based on the following was purchased from BD Transduction Laboratories (San Diego, CA). Anti-␤- evidence: (a) aberrant induction of the Mdr1a (Abcb1a) gene product, P- catenin (C-18), anti-MDR (C-19 and H-241), and anti-actin (C-11) polyclonal glycoprotein, associated with nuclear accumulation of the ␤-catenin protein, antibodies were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, was observed even in nascent microscopic adenomas of Min mice; (b) Mdr1- CA). Immunoblot analyses and immunohistochemistry were performed essen- ؉ ؊ ؊ deficient Min (ApcMin/ Mdr1a/b / ) mice developed significantly fewer intes- tially as described previously (8). For immunofluorescence microscopy, cells ؉ ؉ ؉ tinal polyps than did ApcMin/ Mdr1a/b / mice; and (c) Inhibitors of P- were grown on type-I-collagen-coated coverslips (Asahi Technoglass, Tokyo, glycoprotein, verapamil, and cyclosporin A had a suppressive effect on the in Japan), fixed with 10% buffered formalin, and incubated with anti-␤-catenin vitro polypoid growth of IEC6 expressing stabilized (⌬N89) ␤-catenin protein. monoclonal antibody overnight. After incubation with Alexa Fluor 488-labeled Inhibitors of P-glycoprotein may be included in a novel class of chemopre- goat antimouse IgG (Molecular Probes, Eugene, OR), the coverslips were ventive agents against colorectal carcinogenesis. inspected with a laser scanning confocal microscope (Bio-Rad, Hercules, CA). Reverse Transcription-PCR. Total RNA was prepared from adrenal Introduction gland, normal small intestine, and polyp tissues of Min mice (C57BL/6J- ApcMin/ϩ) with TRIzol (Invitrogen, Carlsbad, CA). A 1-␮g sample of DNase- Mutational inactivation of the tumor suppressor gene APC3 is the I-treated total RNA was reverse transcribed and amplified by PCR. The earliest and most frequent genetic event in colorectal carcinogenesis following PCR primers were used: for Mdr1a, 5Ј-TGAAGCTTGTA- ␤ (1). Its inactivation causes IECs to accumulate cytoplasmic -catenin AATCTAAGGAT-3Ј and 5Ј-TGAAAGAAATGATCCCAAGGAT-3Ј; for protein and allows the formation of complexes between ␤-catenin and Mdr1b, 5Ј-TAATGCTTATGGATCCCAGAGT-3Ј and 5Ј-TTTCATGGTCA- TCF/LEF family transcription factors. Aberrant transactivation of a TCATCTCTTGA-3Ј; for Mdr3, 5Ј-ATTTGAAGTTGAGCTAAGTGAC-3Ј certain set of target genes by the ␤-catenin and TCF4/LEF complexes and 5Ј-ATAGCTATCATCTCAGACAGGA-3Ј; for cytokeratin 19, 5Ј-TT- has been considered crucial for the initiation of intestinal carcinogen- GAGATTGAGCTGCAGTCCCAGCT-3Ј and 5Ј-TTCCCAGGGGAGTCTC- esis, and several downstream targets of the complex have already been GCTGGTAGC-3Ј; for GAPDH (glyceraldehyde-3 phosphate dehydrogenase), identified, including c-myc, PPAR-␦, cyclin-D1, TCF-1, c-jun, fra-1, rodent GAPDH forward and reverse primers (Applied Biosystems (Foster City, matrylisin (MMP-7), gastrin, ectodermal-neural cortex 1, laminin ␥2, CA). PCR products were analyzed by agarose gel electrophoresis and ethidium bromide staining. ITF-2, and axin2 (Axil) (2–7). We demonstrated previously that the ␤ Mdr1 and Apc Compound Mutant Mice. Animal experiments were per- human MDR1 (ABCB1) gene contains multiple -catenin–TCF4- formed in accordance with the guidelines of the National Cancer Center binding elements in its promoter and is an immediate target of the Research Institute (Tokyo, Japan). C57BL/6J male Min (ApcMin/ϩ) mice (12) complex (8). These target genes are likely to be important mediators were obtained from The Jackson Laboratory (Bar Harbor, ME), and FVB of intestinal carcinogenesis and good candidates for chemoprevention female Mdr1a/b double knockout mice (Mdr1aϪ/Ϫ/Mdr1bϪ/Ϫ; Ref. 13) were of colorectal cancer by molecular targeting. However, because with a obtained from Taconic Farms (Germantown, NY). The genotyping of the few exceptions (3, 9–11) the functional connection of these down- animals is described in Fig. 2 and its legends. N6F1 pups were housed under stream target genes with intestinal carcinogenesis has remained un- identical conditions and sacrificed at 15 weeks of age. The gut was filled with explored, in this study, we adopted a genetic approach to clarify the 10% buffered formalin via the anus immediately after sacrifice and then opened longitudinally. After overnight fixation, specimens were stained briefly with 0.5% methylene blue. The numbers and major diameters of polyps in the Received 10/24/02; accepted 1/20/03. small and large intestine were measured in the ϫ20 power field of a dissecting The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with microscope (Nikon, Tokyo, Japan). Formalin-fixed, paraffin-embedded sec- 18 U.S.C. Section 1734 solely to indicate this fact. tions were stained by standard H&E techniques. 1 Supported by grants from the Ministry of Health, Labor, and Welfare; the Ministry Cell Lines and Tetracycline-inducible Retroviral Expression. An im- of Education, Culture, Sports, Science and Technology, Japan; and the Program for mortalized rat small cell line, IEC6 (14), was obtained from the Riken Cell Promotion of Fundamental Studies in Health Sciences of the Organization for Pharma- ceutical Safety and Research of Japan. Y. M. and Y. N. are recipients of a Research Bank (Tsukuba, Japan) and cultivated in DMEM containing 5% Tet-system- Resident Fellowship from the Foundation for Promotion of Cancer Research. approved fetal bovine serum (BD Biosciences Clontech, Palo Alto, CA) and 4 2 To whom requests for reprints should be addressed, at Cancer Proteomics Project, ␮g/ml insulin (Invitrogen). A colorectal cancer cell line, DLD1, was obtained National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, from the Health Science Research Resources Bank (Osaka, Japan; Ref. 8). Japan. Phone: 81-3-3542-2511, extension 4054; Fax: 81-3-3547-5298; E-mail: [email protected]. We used the RevTet-Off gene expression system (BD Biosciences Clon- 3 Abbreviations used are: APC, adenomatous polyposis coli; MDR, multidrug resist- tech) to introduce the tetracycline-regulatory element, tTA, and subsequently ance; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IEC, intestinal epithelial cell; the Rev-TRE carrying AU1-tagged human ␤Ϫcatenin cDNA lacking the FAP, familial adenomatous polyposis; TCF, T-cell factor; LEF, lymphoid enhancer factor; NH2-terminal 89 amino acids (15), into IEC6 cells. Details of preparation of ABC, ATP-binding cassette; NSAID nonsteroidal anti-inflammatory drug; Min, multiple ␤ ⌬ intestinal neoplasia; Mom1, modifier of multiple intestinal neoplasia-1; Mom, modifier of the pRev-TRE -catenin N89 plasmid construct are available on request. multiple intestinal neoplasia; PAF, platelet-activating factor; Dox, doxycycline. Cells were infected for 24 h in the presence of 8 ␮g/ml Polybrene (Sigma, St. 895 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2003 American Association for Cancer Research. Ϫ Ϫ ϩ SUPPRESSION OF POLYPOSIS IN MDR1 / APCMIN/ MICE Fig. 1. Increased expression of P-glycoprotein in intestinal adenoma of Min mice. Immunoperoxi- dase staining was performed on serial sections ex- posed to anti-␤-catenin (C-18; A, B, and E) and anti-P-glycoprotein (C-19; C, D, and F) polyclonal antibodies. A and B, expression of ␤-catenin pro- tein in an adenomatous polyp of a Min mouse (C57BL/6J-ApcMin/ϩ). Original magnification: ϫ40 (A) and ϫ200 (B). C and D, expression of P-glycoprotein in the same polyp as in A and B. Original magnification: ϫ40 (C) and ϫ200 (D). E and F, ␤-catenin (E) and P-glycoprotein (F) expres- sion in a univillous adenoma. Original magnifica- tion: ϫ100. G, mRNA expression of Mdr1a, Mdr1b, Mdr3, cytokeratin 19 (Cy19), and GAPDH in adrenal gland (Ad.), normal small intestinal (N), and adenomatous (T) tissue of Min mice. Cyto- keratin 19 was included to monitor the endodermal contribution (6). GAPDH was included to monitor the integrity of the cDNA templates. Louis, MO) with conditioned medium containing ecotropic retroviral particles, Dual Luciferase Reporter Assay. We used a pair of luciferase reporter as described previously (16) and cloned by limiting dilution with uninfected constructs, TOP-FLASH and FOP-FLASH (Upstate, Placid, NY), to evaluate cells as feeder layers. TCF/LEF transcriptional activity (16). Cells
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