Abstract
4-vinyl-2, 6-dimethoxyphenol (canolol) is an antioxidant phenolic compound extracted from crude canola oil. In current research, K19-C2mE transgenic mice, developing hyperplastic tumors spontaneously in the glandular stomach, were used to study the mechanisms involved in the anti-inflammation and anti-tumor effects of canolol. Tg mice receiving canolol diet had a reduced tumor incidence, to 41.2%, compared with Non-treatment Tg mice, 77.8% of which had gastric tumor (P=0.002). Besides that, the mean tumor diameter was decreased from 6.5mm to 4.5mm (P<0.001) after canolol administration. COX-2/PGE2 pathway is known to play pivotal role in inflammation-induced gastric tumorigenesis. The neutrophils and lymphocytes infiltration was suppressed significantly, and the mRNA levels of the proinflammatory cytokines COX-2, IL-1β and IL-12b were also downregulated in gastric mucosa. Additionally, immunohistochemical analysis showed that COX-2, EP2, Gαs and β-catenin, key factors involving in PGE2 signal transduction, were positive staining with higher H scores in Non-treatment Tg mice, while the expressions were suppressed significantly by 0.1% canolol (P<0.001). In addition, tumor-suppressor miR-7 was reactivated after canolol administration, and COX-2 was showed to be a functional target of miR-7 to suppress the tumor progression. In conclusion, canolol could inhibit the gastritis-related tumor initiation and progression, and the suppression effect was correlated with the blocking up of canonical COX-2/PGE2 signaling pathway and might be regulated by miR-7.
Highlights
Gastric cancer remains the fourth most commonly diagnosed cancer and is the second leading cause of cancer related deaths worldwide
Among various inflammatory networks involved in gastric carcinogenesis, the COX-2/PGE2 pathway was identified as a key player firstly[2]
The tumors size in both groups was measured using vernier caliper, the mean diameter of tumor in Tg group was 6.5mm, while it decreased into 4.5mm after 0.1% canolol administration (P
Summary
Gastric cancer remains the fourth most commonly diagnosed cancer and is the second leading cause of cancer related deaths worldwide. Among various inflammatory networks involved in gastric carcinogenesis, the COX-2/PGE2 pathway was identified as a key player firstly[2]. The transgenic mouse was recognized as the ideal model to investigate the precise role of COX-2/PGE2 pathway in gastric tumor initiation and progression. There are four GPCRs for PGE2, namely, EP1–4[8], and they are linked to different signaling pathway, whereas, EP2 can couple with Gαs to stimulate adenylyl cyclase (AC) and increase intracellular cAMP level[9]. Β-catenin is a key component of PGE2 signaling pathway, and the translocation and accumulation of β-catenin in nuclear combined with TCF/LEF transcription factor and influenced the downstream gene (i.e. COX-2, IL-8, VGFR) expression. The main object of our research was to examine the inhibitory effects of canolol on gastric tumor initiation and progression in vivo, and to further investigate the possible mechanisms involving PGE2 signal transduction via miRNA regulation
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