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

Abstract

BackgroundSilence 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.MethodsThe 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.ResultsRes 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.ConclusionRes 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 materialThe online version of this article (doi:10.1186/s12885-015-1958-6) contains supplementary material, which is available to authorized users.

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

“…A broad spectrum of miRNAs has been identified to be involved in the etiology of AD and cancer. Among them, miR-34c, as a tumor suppressor and a critical mediator in the p53 pathway (Beard et al, 2016;Cortez et al, 2016), can reduce cell growth, induce apoptosis, and affect cell migration (Tao et al, 2016;Yang et al, 2015). It is reported that the levels of miR-34c were increased in circulating blood samples of patients with AD compared to age-matched normal controls (Bhatnagar et al, 2014) .…”

Resveratrol and Its Nanoformulation Attenuate Growth and the Angiogenesis of Xenograft and Orthotopic Colon Cancer Models

“…In our study, RSV reduced the growth and bioluminescent signals of orthotopic colon tumor (COLO205-luc). In another study in xenograft mice, a combination of RSV and oxaliplatin was more effective at inhibiting tumor growth than RSV and oxaliplatin alone of implanted colon cancer [29,30].…”

Biological Activities of Resveratrol against Cancer

“…A research by Feng demonstrated that RSV significantly inhibited cell proliferation of colon cancer cells (HCA-17, SW480, HT29) cells by inducing apoptosis and inhibiting expression of cyclooxygenase-2 and prostaglandin receptor [82]. Yang found that RSV suppressed colorectal cancer by upregulating miR-34c which successively was able to inhibit its target KITLG, this effect was accentuated in presence of p53 compared to p53-knockdown cells in vitro and in vivo [83]. RSV significantly showed anti-cancer effect by upregulating expression level of BMP9 in LoVo cells, moreover, via mitochondria apoptosis pathway triggered by production of ROS [101].…”