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Research Articles

Lack of STAT6 Attenuates Inflammation and Drives Protection against Early Steps of Colitis-Associated Colon Cancer

Sonia A. Leon-Cabrera, Emmanuel Molina-Guzman, Yael G. Delgado-Ramirez, Armando Vázquez-Sandoval, Yadira Ledesma-Soto, Carlos G. Pérez-Plasencia, Yolanda I. Chirino, Norma L. Delgado-Buenrostro, Miriam Rodríguez-Sosa, Felipe Vaca-Paniagua, Federico Ávila-Moreno, Emma B. Gutierrez-Cirlos, Luis E. Arias-Romero and Luis I. Terrazas
Sonia A. Leon-Cabrera
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
2Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Emmanuel Molina-Guzman
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Yael G. Delgado-Ramirez
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Armando Vázquez-Sandoval
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Yadira Ledesma-Soto
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Carlos G. Pérez-Plasencia
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Yolanda I. Chirino
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Norma L. Delgado-Buenrostro
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Miriam Rodríguez-Sosa
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Felipe Vaca-Paniagua
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
3Laboratorio Nacional en Salud, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Mexico.
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Federico Ávila-Moreno
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Emma B. Gutierrez-Cirlos
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Luis E. Arias-Romero
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
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Luis I. Terrazas
1Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.
3Laboratorio Nacional en Salud, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Mexico.
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  • For correspondence: literrazas@unam.mx
DOI: 10.1158/2326-6066.CIR-16-0168 Published May 2017
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    Figure 1.

    STAT6-deficient animals show decreased susceptibility to AOM/DSS-induced CAC. A, DAI on days 20, 40, and 68 following treatment with 12.5 mg/kg AOM injection and 2% DSS in drinking water per 7 days followed by 7 days of regular water. B, Percent change in body weight compared with the baseline weight in WT and STAT6–/– mice. C, Percentage of tumor-free mice during AOM-DSS treatment in WT and STAT6–/– animals. D, Representative photographs of colons from WT and STAT6–/– mice on day 68 after the AOM/DSS tumor induction protocol. WT mice displayed shortened and edematous colons with nodular and polypoid tumors compared with STAT6–/– mice. E, Number and F, size of tumors in WT and STAT6–/– mice on day 68 after AOM/DSS treatment. G, Colons from WT and STAT6–/– mice were obtained during animal necropsy and weighed. The data are expressed as the mean ± SE from 5 mice per group and are representative of three independent experiments. **, P < 0.01.

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    Figure 2.

    WT mice exhibit more severe histopathologic alterations than STAT6–/– mice following AOM/DSS-induced CAC. A, Representative H&E-stained colonic sections from WT and STAT6–/– mice on days 20, 40, and 68 after AOM/DSS treatment. WT mice displayed extensive colonic mucosal erosion, ulceration, severe crypt damage, and massive infiltration of inflammatory cells into the colonic mucosa compared with STAT6–/– mice. This effect was more pronounced in the distal colon compared with the proximal colon. B, Alcian blue stain of colon tissue (top) from WT and STAT6–/– animals for visualizing goblet cells on days 20, 40, and 68 after AOM/DSS treatment. Quantification of goblet cells at day 68 (bottom) from at least 20 crypts per region in five fields in four different slides per animal. Data are expressed as mean ± SE from 5 mice per group and are representative of three independent experiments. **, P < 0.01

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    Figure 3.

    β-catenin and COX-2 expression is delayed in the colons of STAT6–/– animals. Immunohistochemical stain and quantification for (A) β-catenin and (B) COX-2 in the colon tissue of WT and STAT6–/– mice on days 20, 40, and 68 of the AOM/DSS tumor induction protocol. Quantification of the tumor cells positive for β-catenin (A) and COX-2 (B) was conducted as described in the Materials and Methods section. The data are expressed as the mean ± SE from 5 mice per group and are representative of three independent experiments. Statistical significance was determined by one-way ANOVA with Tukey test *, P < 0.05; **, P < 0.001; ***, P < 0.0001.

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    Figure 4.

    Increased apoptosis and reduced epithelial cell proliferation in STAT6–/– mice during early CAC development. Evaluation of (A) cell proliferation by Ki67 immunostaining and (B) apoptosis by TUNEL assay in the colonic tissues of WT and STAT6–/– mice at the indicated times during CAC development. The percentage of (C) Ki67+ cells was conducted as described in the Materials and Methods section. D, Fluorescence quantification in colon tissue of TUNEL+ cells. The data are presented as the percentage of mean fluorescence, which was expressed as arbitrary units. The data are expressed as the mean ± SE from 5 mice per group in three independent experiments. *, P < 0.05; **, P < 0.01.

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    Figure 5.

    Interleukin and chemokine detection during CAC development. A, IL17A, B, TNFα and C, IL10 cytokine mRNA expression in the colonic tissues of WT and STAT6–/– mice on days 20, 40, and 68 after AOM/DSS treatment. D, IL17A and E, IL10 concentrations in supernatants of mesenteric lymphoid cells stimulated with antibodies to CD3/CD28 (2 μg/mL) for 24 hours from WT and STAT6–/– mice on days 20, 40, and 68 after AOM/DSS treatment were measured by ELISA. F, CCL9, G, CCL25, and H, CXCR2 mRNA expression in the colon mucosa on day 68. The data are expressed as the mean ± SE from 5 mice per group and are representative of three independent experiments. *, P < 0.05.

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    Figure 6.

    STAT6 deficiency reduces the percentages of circulating inflammatory monocytes and granulocytes during CAC. Representative flow cytometry dot plots for CD11b+ living cells isolated from the circulation of WT and STAT6–/– mice. Flow cytometric analysis was performed with Ly6G and Ly6C markers expressed in the cell surface of circulating cells. A, Representative dot plots and graph display the proportion of CD11b+Ly6ChiCCR2+ monocytes gated on CD11b+ populations living cells isolated from the circulation of WT and STAT6–/– mice on day 68 after AOM administration. B, Representative dot plots and graph display CD11b+Ly6ClowLy6G+ cells from STAT6–/– mice compared with WT animals on days 20, 40, and 68 after AOM/DSS tumor induction protocol. C, Percentage of CD8+ and CD4+ cells gated on CD3+ living cells isolated from the circulation of WT and STAT6–/– mice on day 68 after AOM/DSS administration. The data are representative of two independent experiments that included n = 4–5 mice/group. Values are expressed as the mean ± SE. *, P < 0.05.

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    Figure 7.

    In vivo STAT6 inhibition reduces colonic tumor load. A, WT mice were treated with the STAT6 inhibitor AS 1517499 or equivalent volume of vehicle (VHC) every third day during all AOM/DSS treatment and sacrificed at days 20, 40, and 68. B, DAI; C, Change of body weight; D, Number of tumors at day 68; E, Percentage of tumor-free mice; F, H&E (left) and Alcian blue (right) stained colonic sections from WT mice treated with the STAT6 inhibitor AS 1517499 on days 20 and 40 after AOM/DSS administration. G, Change in the phosphorylation of STAT6 after treatment with STAT6 inhibitor AS 1517499 determined by immunoblotting. Higher levels of phosphorylated STAT6 (pSTAT6) were observed in WT and WT+VHC mice on day 20 after AOM/DSS administration. The data are expressed as the mean ± SE from 5 mice per group and are representative of two independent experiments. a, (week 2 and 3 vs. week 0 in the WT group). *, P < 0.05; **, P < 0.001.

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Cancer Immunology Research: 5 (5)
May 2017
Volume 5, Issue 5
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Lack of STAT6 Attenuates Inflammation and Drives Protection against Early Steps of Colitis-Associated Colon Cancer
Sonia A. Leon-Cabrera, Emmanuel Molina-Guzman, Yael G. Delgado-Ramirez, Armando Vázquez-Sandoval, Yadira Ledesma-Soto, Carlos G. Pérez-Plasencia, Yolanda I. Chirino, Norma L. Delgado-Buenrostro, Miriam Rodríguez-Sosa, Felipe Vaca-Paniagua, Federico Ávila-Moreno, Emma B. Gutierrez-Cirlos, Luis E. Arias-Romero and Luis I. Terrazas
Cancer Immunol Res May 1 2017 (5) (5) 385-396; DOI: 10.1158/2326-6066.CIR-16-0168

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Lack of STAT6 Attenuates Inflammation and Drives Protection against Early Steps of Colitis-Associated Colon Cancer
Sonia A. Leon-Cabrera, Emmanuel Molina-Guzman, Yael G. Delgado-Ramirez, Armando Vázquez-Sandoval, Yadira Ledesma-Soto, Carlos G. Pérez-Plasencia, Yolanda I. Chirino, Norma L. Delgado-Buenrostro, Miriam Rodríguez-Sosa, Felipe Vaca-Paniagua, Federico Ávila-Moreno, Emma B. Gutierrez-Cirlos, Luis E. Arias-Romero and Luis I. Terrazas
Cancer Immunol Res May 1 2017 (5) (5) 385-396; DOI: 10.1158/2326-6066.CIR-16-0168
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