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Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo

BACKGROUND: Silence of the tumor suppressor miR-34c is implicated in the development of colorectal cancer (CRC). For the past few years, Resveratrol (Res) has been introduced to oncotherapies alone or with traditional chemotherapeutic drugs. However, the study of molecular mechanism involved in the...

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Autores principales: Yang, Shu, Li, Wenshuai, Sun, Haimei, Wu, Bo, Ji, Fengqing, Sun, Tingyi, Chang, Huanhuan, Shen, Ping, Wang, Yaxi, Zhou, Deshan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682213/
https://www.ncbi.nlm.nih.gov/pubmed/26674205
http://dx.doi.org/10.1186/s12885-015-1958-6
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author Yang, Shu
Li, Wenshuai
Sun, Haimei
Wu, Bo
Ji, Fengqing
Sun, Tingyi
Chang, Huanhuan
Shen, Ping
Wang, Yaxi
Zhou, Deshan
author_facet Yang, Shu
Li, Wenshuai
Sun, Haimei
Wu, Bo
Ji, Fengqing
Sun, Tingyi
Chang, Huanhuan
Shen, Ping
Wang, Yaxi
Zhou, Deshan
author_sort Yang, Shu
collection PubMed
description BACKGROUND: Silence of the tumor suppressor miR-34c is implicated in the development of colorectal cancer (CRC). For the past few years, Resveratrol (Res) has been introduced to oncotherapies alone or with traditional chemotherapeutic drugs. However, the study of molecular mechanism involved in the anti-CRC effect of Res is still ongoing. METHODS: The anti-CRC effect of Res alone or with Oxaliplatin (Oxa) was determined by cell viability assay, soft agar colony formation assay, flow cytometry and real-time cellular analyzer in HT-29 (p53(+)) and HCT-116 (p53(−)) CRC cell lines. Expressions of miR-34c and its targets were detected by qPCR and/or western blot. To evaluate the role of miR-34c in anti-CRC effect by Res alone or with Oxa, miR-34c was up or down-regulated by lentiviral mediation or specific inhibitor, respectively. To investigate how miR-34c was increased by Res, the methylation status of miR-34c promoter was detected by MSP. The tumor bearing mouse model was established by subcutaneous injection of HCT-116 cells to assess anti-CRC effect of Res alone or with Oxa in vivo. IL-6 and TNF-α in xenografts were detected by ELISA. RESULTS: Res inhibited cell viability, proliferation, migration and invasion as well as promoted apoptosis both in HT-29 and HCT-116 CRC cells. The anti-CRC effect of Res was partially but specifically through up-regulating miR-34c which further knocked down its target KITLG; and the effect was enhanced in the presence of p53 probably through inactivating PI3K/Akt pathway. Besides, Res sensitized CRC cells to Oxa in a miR-34c dependent manner. The xenograft experiments showed that exposure to Res or Oxa suppressed tumor growth; and the efficacy was evidently augmented by the co-treatment of Res and Oxa. Likewise, miR-34c level was elevated in xenografts of Res-treated mice while the KITLG was decreased. Finally, Res clearly reduced IL-6 in xenografts. CONCLUSION: Res suppressed CRC by specifically activating miR-34c-KITLG in vitro and in vivo; and the effect was strengthened in the presence of p53. Besides, Res exerted a synergistic effect with Oxa in a miR-34c dependent manner. We also suggested that Res-increased miR-34c could interfere IL-6-triggered CRC progression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1958-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-46822132015-12-18 Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo Yang, Shu Li, Wenshuai Sun, Haimei Wu, Bo Ji, Fengqing Sun, Tingyi Chang, Huanhuan Shen, Ping Wang, Yaxi Zhou, Deshan BMC Cancer Research Article BACKGROUND: Silence of the tumor suppressor miR-34c is implicated in the development of colorectal cancer (CRC). For the past few years, Resveratrol (Res) has been introduced to oncotherapies alone or with traditional chemotherapeutic drugs. However, the study of molecular mechanism involved in the anti-CRC effect of Res is still ongoing. METHODS: The anti-CRC effect of Res alone or with Oxaliplatin (Oxa) was determined by cell viability assay, soft agar colony formation assay, flow cytometry and real-time cellular analyzer in HT-29 (p53(+)) and HCT-116 (p53(−)) CRC cell lines. Expressions of miR-34c and its targets were detected by qPCR and/or western blot. To evaluate the role of miR-34c in anti-CRC effect by Res alone or with Oxa, miR-34c was up or down-regulated by lentiviral mediation or specific inhibitor, respectively. To investigate how miR-34c was increased by Res, the methylation status of miR-34c promoter was detected by MSP. The tumor bearing mouse model was established by subcutaneous injection of HCT-116 cells to assess anti-CRC effect of Res alone or with Oxa in vivo. IL-6 and TNF-α in xenografts were detected by ELISA. RESULTS: Res inhibited cell viability, proliferation, migration and invasion as well as promoted apoptosis both in HT-29 and HCT-116 CRC cells. The anti-CRC effect of Res was partially but specifically through up-regulating miR-34c which further knocked down its target KITLG; and the effect was enhanced in the presence of p53 probably through inactivating PI3K/Akt pathway. Besides, Res sensitized CRC cells to Oxa in a miR-34c dependent manner. The xenograft experiments showed that exposure to Res or Oxa suppressed tumor growth; and the efficacy was evidently augmented by the co-treatment of Res and Oxa. Likewise, miR-34c level was elevated in xenografts of Res-treated mice while the KITLG was decreased. Finally, Res clearly reduced IL-6 in xenografts. CONCLUSION: Res suppressed CRC by specifically activating miR-34c-KITLG in vitro and in vivo; and the effect was strengthened in the presence of p53. Besides, Res exerted a synergistic effect with Oxa in a miR-34c dependent manner. We also suggested that Res-increased miR-34c could interfere IL-6-triggered CRC progression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1958-6) contains supplementary material, which is available to authorized users. BioMed Central 2015-12-16 /pmc/articles/PMC4682213/ /pubmed/26674205 http://dx.doi.org/10.1186/s12885-015-1958-6 Text en © Yang et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Yang, Shu
Li, Wenshuai
Sun, Haimei
Wu, Bo
Ji, Fengqing
Sun, Tingyi
Chang, Huanhuan
Shen, Ping
Wang, Yaxi
Zhou, Deshan
Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo
title Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo
title_full Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo
title_fullStr Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo
title_full_unstemmed Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo
title_short Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo
title_sort resveratrol elicits anti-colorectal cancer effect by activating mir-34c-kitlg in vitro and in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682213/
https://www.ncbi.nlm.nih.gov/pubmed/26674205
http://dx.doi.org/10.1186/s12885-015-1958-6
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