Abstract
Delphinidin is a flavonoid belonging to dietary anthocyanidin family that has been reported to possess diverse anti-tumoral activities. However, the effects of delphinidin on colorectal cancer (CRC) cells and the underlying mechanisms are not fully understood. Thus, we aimed to investigate the anti-cancer activity of delphinidin in CRC cells and the underlying molecular mechanisms. The effects of delphinidin on the viability, metastatic characteristics, signaling, and microRNA (miR) profile of human CRC cell lines used were analyzed. In vivo metastasis was also evaluated using xenograft animal models. Our findings showed that delphinidin (<100 μM) inhibited the colony formation of DLD-1, SW480, and SW620 cells, but non-significantly affected cell viability. Delphinidin also suppressed the migratory ability and invasiveness of the tested CRC cell lines, downregulated integrin αV/β3 expression, inhibited focal adhesion kinase (FAK)/Src/paxillin signaling, and interfered with cytoskeletal construction. Analysis of the miR expression profile revealed a number of miRs, particularly miR-204-3p, that were significantly upregulated and downregulated by delphinidin. Abolishing the expression of one upregulated miR, miR-204-3p, with an antagomir restored delphinidin-mediated inhibition of cell migration and invasiveness in DLD-1 cells as well as the αV/β3-integrin/FAK/Src axis. Delphinidin also inhibited the lung metastasis of DLD-1 cells in the xenograft animal model. Collectively, these results indicate that the migration and invasion of CRC cells are inhibited by delphinidin, and the mechanism may involve the upregulation of miR-204-3p and consequent suppression of the αV/β3-integrin/FAK axis. These findings suggest that delphinidin exerts anti-metastatic effects in CRC cells by inhibiting integrin/FAK signaling and indicate that miR-204-3p may play an important role in CRC metastasis.
Highlights
Colorectal cancer (CRC) is a leading cause of death in countries worldwide, including Taiwan, and it is the second and third most common cancer in women and men, respectively[1]
MicroRNAs are short (22–24 nucleotide) non-coding RNAs that bind to the 3′-untranslated region of coding RNAs by base pairing, which results in termination of protein translation or degradation of messenger RNA14. miRs have been implicated in embryonic development[15,16], cellular homeostasis[17,18], physiopathological conditions[19,20], and dysregulated expression of oncogenic genes involved in various cancers, including renal cell carcinoma[21], ovarian cancer[22], and hepatocellular carcinoma23. miR dysregulation has been shown to be involved in the induction of epithelial-mesenchymal transition (EMT) in various tumors[24,25]
Since the viability of colorectal cancer (CRC) cells was not affected by delphinidin, we explored its effects on colony formation and cell adhesion
Summary
Colorectal cancer (CRC) is a leading cause of death in countries worldwide, including Taiwan, and it is the second and third most common cancer in women and men, respectively[1]. The acquisition of cell adhesion, migratory ability, and invasiveness plays a pivotal role in the metastasis of CRC4. These metastatic characteristics of CRC cells could be important treatment targets. MiR dysregulation has been shown to be involved in the induction of epithelial-mesenchymal transition (EMT) in various tumors[24,25]. This evidence indicates that uncontrolled miR expression may be associated with carcinogenesis, cancer progression, and tumor metastasis. The related signaling cascades were evaluated by western blotting, and the miR expression profile was analyzed by microarray and quantitative real-time reverse transcription poly chain reaction (qRT-PCR)
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