Polyphenols from Hippophae rhamnoides suppressed colon cancer growth by regulating miRNA-mediated cell cycle arrest and apoptosis in vitro and in vivo

Abstract

• HPs60 treatment result in alteration of miRNA expression profile, among which, 29 up-regulated and 9 down-regulated. • Hsa-miR-195-5p, hsa-miR-497-5p and hsa-miR-1247-3p are the reliable targets of HPs60. • HPs60 up-regulate miR-195-5p/497-5p expression, suppresses that of cyclin D1/2/2 and cyclin E1, then leads to G1 arrest. • HPs60 promotes miR-1247-3p-mediated expression of caspase 2, and inhibits that of miR-195-5p/497-5p-mediated Bcl-2, ultimately induces apoptosis. Colorectal cancer (CRC) is the most common gastrointestinal cancer. Hippophae rhamnoides are reported to possess a variety of active substances. MiRNAs are new therapeutic targets. Here, it found that Hippophae rhamnoides L. polyphenols (named as HPs60) exhibited significant anti-colon cancer activity in vitro and in vivo . And the main components were identified by LC-MS as kaempferol and its derivatives. Subsequently, by RNA-sequencing and searching GEO and TCGA database, three reliable miRNAs including hsa-miR-195-5p, hsa-miR-497-5p and hsa-miR-1247-3p were eventually screened. As expected, hsa-miR-195-5p and hsa-miR-497-5p were upregulated upon HPs60 treatment, while hsa-miR-1247-3p was downregulated. Furthermore, HPs60 remarkably suppressed the expression of cyclinD1, cyclinD2, cyclinD3, cyclinE1 and Bcl-2, which are the targets of miR-195-5p and miR-497-5p. Correspondingly, HPs60 promoted expression of caspase-2, a target gene of miR-1247-3p. All of these results suggest that HPs60 may explore as natural bioactive ingredients and reveal the potential therapeutic targets responsible for HPs60 against CRC.