Wumei Pill Ameliorates AOM/DSS-Induced Colitis-Associated Colon Cancer through Inhibition of Inflammation and Oxidative Stress by Regulating S-Adenosylhomocysteine Hydrolase- (AHCY-) Mediated Hedgehog Signaling in Mice

Abstract

Wumei Pill (WMP) is a traditional Chinese herbal formulation and widely used to treat digestive system diseases in clinical. S-Adenosylhomocysteine hydrolase (AHCY) can catalyze the hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine in living organisms, and its abnormal expression is linked to the pathogenesis of many diseases including colorectal cancer (CRC). A previous study reported that WMP could prevent CRC in mice; however, the underlying mechanisms especially the roles of AHCY in WMP-induced anti-CRC remain largely unknown. Here, we investigated the regulatory roles and potential mechanisms of AHCY in WMP-induced anti-CRC. WMP notably alleviated the azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colitis-associated colon cancer (CAC) in mice. Besides, WMP inhibited the inflammation and oxidative stress in AOM/DSS-induced CAC mice. AHCY was high expression in clinical samples of colon cancer compared to the adjacent tissues. WMP inhibited the AHCY expression in AOM/DSS-induced CAC mice. An in vitro study found that AHCY overexpression induced cell proliferation, colony formation, invasion, and tumor angiogenesis, whereas its knockdown impaired its oncogenic function. AHCY overexpression enhanced, while its knockdown weakened the inflammation and oxidative stress in colon cancer cells. Interestingly, WMP potently suppressed the hedgehog (Hh) signaling in AOM/DSS-induced CAC mice. A further study showed that AHCY overexpression activated the Hh signaling while AHCY knockdown inactivated the Hh signaling. Moreover, activation of the Hh signaling reversed the effect of AHCY silencing on inflammation and oxidative stress in vitro. In conclusion, WMP alleviated the AOM/DSS-induced CAC through inhibition of inflammation and oxidative stress by regulating AHCY-mediated hedgehog signaling in mice. These findings uncovered a potential molecular mechanism underlying the anti-CAC effect of WMP and suggested WMP as a promising therapeutic candidate for CRC.

Inhibition of Ribosomal RNA Processing 15 Homolog (RRP15) Suppressed Tumor Growth, Invasion and Epithelial to Mesenchymal Transition (EMT) of Colon Cancer

“…Here, we determined RRP15 expression in an AOM/DSS-induced mice CAC model. Consistent with the previous studies [ 12 , 13 ], including ours [ 14 ], obvious tumorigenesis and shorter colon length were observed in the AOM/DSS-treated group than in the untreated group ( Figure 2 A). Interestingly, a significant increase in RRP15 expression was observed in the AOM/DSS-treated group than in the untreated group ( Figure 2 B).…”

“…To establish the AOM/DSS-induced mice CAC model, the detailed protocol can be referred to in our previous report [ 14 ]. The experimental procedures were permitted by the Institutional Animal Ethical Committee of Nantong University on 7 September 2020 (project identification code: S20200907-306) and performed by abiding to the NIH Guidelines for Care and Use of Laboratory Animals.…”

Suppression of microRNA-222-3p ameliorates ulcerative colitis and colitis-associated colorectal cancer to protect against oxidative stress via targeting BRG1 to activate Nrf2/HO-1 signaling pathway

“…Further results showed that inhibiting miR-222-3p reduced the levels of ROS and MDA in IECs, increased the level of GSH-Px, and reduced the levels of the inflammatory factors IL-1b and TNF-a in the supernatants of IECs (Figures 8L-P). Previous studies also showed that in the context of oxidative damage in CAC mice, the activities of the antioxidant enzymes GSH-Px and SOD in colon tissue were significantly reduced, and ROS and MDA levels were significantly increased (9,62). However, increasing the expression of Nrf2 and HO-1 can increase the activity of the antioxidant enzyme SOD, reduce the levels of MDA, inhibit the levels of the inflammatory markers NF-kB, TNF-a, IL-1b and MPO in CAC mice, and have a certain preventive effect on the occurrence of CAC (63,64).…”

Common mechanisms of Wumei pills in treating ulcerative colitis and type 2 diabetes: Exploring an integrative approach through network pharmacology

“…WMP is widely used in clinical practice, and numerous researchers have explored its mechanisms. [14,[20][21][22][23] However, there is currently a gap in research concerning the common mechanisms of action of WMP in treating both UC and T2DM.…”