Biejiajian Pill Inhibits Carcinogenesis and Metastasis via the Akt/GSK-3β/Snail Signaling Pathway in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is among the most usual cancers globally. In China, Biejiajian pill (BJJP), Traditional Chinese Medicine clinical prescription, is broadly utilized for the prevention and therapy of HCC. However, the mechanisms by which BJJP exerts its effects on the prevention of tumor invasion and metastasis are still largely unknown. In this study, in vitro multiple hepatic cancer cell lines and an in vivo xenograft mice model were used to validate the preventive effects and molecular mechanisms of BJJP in HCC. We established that BJJP significantly repressed the proliferation, metastasis and infiltration of HCC cells. Furthermore, BJJP remarkably suppressed HCC cell migration, as well as invasion via epithelial-mesenchymal transition (EMT) by modulating Snail expression, which was associated with the repression of Akt/GSK-3β/Snail signaling axis activation. In vivo HCC xenograft results indicated that BJJP delayed HCC development and efficiently inhibited lung metastasis. Taken together, BJJP was shown to be an effective therapeutic agent against HCC through repression of the Akt/GSK-3β/Snail signaling cascade and EMT.

Biejiajian Pill Promotes the Infiltration of CD8+ T Cells in Hepatocellular Carcinoma by Regulating the Expression of CCL5

“…BJJP is a canonical formula from "The Synopsis of Golden Chamber" that is made up of 23 ingredients and is widely used in TCM for the treatment of HCC. A previous study by our research group showed that the main components of BJJP were wogonin, zerumbone, ursolic acid, resveratrol and 6gingerol (Sun et al, 2021), all of which have been reported to regulate tumor immunity. Notably, wogonin was shown to have immune-modulatory effects as it regulated the function of effector T cells (Fan et al, 2020).…”

“…Previous study found that BJJP exerted a tight inhibitory influence on the progression of HCC by the inhibition of EMT, which plays important role in hepatocellular carcinoma (Li et al, 2021;Sun et al, 2021). It was reported that EMT signature is inversely associated with T-cell infiltration, which promote tumor cell to escape from immune system defense (Chae et al, 2018;Aghajani et al, 2020).…”

“…Serum-containing BJJP was prepared according to a previously published protocol (Sun et al, 2021). The rats were randomly divided into the BJJP-low dose (L) and BJJP-high-dose (H) (0.55 and 2.2 g/kg, respectively, dissolved in sterilized normal saline) and negative control (NC) groups.…”

“…The formula was originally used to treat hepatosplenomegaly caused by malaria, with multiple benefits, including promoting a healthy qi, removing toxins, dissolving knots and promoting blood circulation to remove blood stasis (Xu and Liu, 2020). It was also shown that BJJP inhibits the growth and invasiveness of HCC cell lines by targeting different cellular signaling pathways, including Wnt/β-catenin (Sun et al, 2014), RhoA/ROCK (An et al, 2018) and Akt/GSK-3β/Snail (Sun et al, 2021). Its molecular mechanism was also associated with the inhibition of Epithelial-mesenchymal transition (EMT), which promoted tumor cells migration and affected the recurrence and prognosis of HCC (Li et al, 2021).…”

Potential Mechanisms of Biejiajian Pill in the Treatment of Diabetic Atherosclerosis Based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation

“…Biejiajian pill (BJJP) originated from Synopsis of Golden Chamber, a traditional Chinese medicine clinical prescription, is broadly utilized for the prevention and therapy of hepatocellular carcinoma [5], so the research on BJJP mainly focused on digestive disease. In recent years, some studies have found that BJJP has a significant effect on diabetic atherosclerosis.…”