Gallic Acid Suppressed Tumorigenesis by an LncRNA MALAT1-Wnt/β-Catenin Axis in Hepatocellular Carcinoma

Abstract

Gallic acid (3,4,5-trihydroxybenzoic acid; GA), a natural phenolic acid, is abundantly found in numerous natural products. Increasing evidence have demonstrated that GA plays anti-cancer roles in multiple cancers. However, its anti-tumor effects on hepatocellular carcinoma (HCC) and the underlying mechanism remain obscure. In the present study, we found that GA suppressed the in vitro cell viability and metastasis and inhibited the in vivo tumor growth of HCC cells. The underlying mechanism was further to investigate and it was showed that GA suppressed the expression of β-catenin and led to the functional inactivation of Wnt/β-catenin signaling. As a kind of significant regulators, the long noncoding RNA molecules (lncRNAs) have attracted widespread attentions for their critical roles in diverse biological process and human diseases. To further identify which lncRNA participated this GA-mediated process, several lncRNAs related to Wnt/β-catenin signaling were chosen for examination of their expression profiling in the GA-treated HCC cells. Of which, Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) was the most promising candidate. And moreover, MALAT1 was significantly down-regulated by GA. Its overexpression partially reversed the GA-induced the inhibitory effects on cell proliferation and metastasis; and successfully abolished the suppressive effect of GA on Wnt/β-catenin signaling. In conclusion, our results indicated that GA suppressed tumorigenesis in vitro and in vivo by the MALAT1-Wnt/β-catenin signaling axis, suggesting that GA has great potential to be developed as a chemo-prevention and chemotherapy agent for HCC patients.

Gallic acid induces osteoblast differentiation and alleviates inflammatory response through GPR35/GSK3β/β‐catenin signaling pathway in human periodontal ligament cells

“…Interestingly, the previous studies showed that GA suppresses β‐catenin expression and inactivates Wnt/β‐catenin signaling in tumor cells while our study indicated that GA induced β‐catenin expression in hPDL cells 34,35 . Similarly, several natural compounds have recently been described as inhibitors of the Wnt/β‐catenin signaling pathway in tumor cells such as quercetin and fisetin; however, when treat these compounds in stem cell or pre‐osteoblasts, they induced Wnt/β‐catenin pathway 36–39 .…”

“…Interestingly, the previous studies showed that GA suppresses β-catenin expression and inactivates Wnt/β-catenin signaling in tumor cells while our study indicated that GA induced β-catenin expression in hPDL cells. 34,35 Similarly, several natural compounds have recently been described as inhibitors of the Wnt/β-catenin signaling pathway in tumor cells such as quercetin and fisetin; however, when treat these compounds in stem cell or pre-osteoblasts, they induced Wnt/β-catenin pathway. [36][37][38][39] All the mentioned compounds include GA have multiple targets involved in both upstream and downstream events of the Wnt/β-catenin signaling instead of direct interaction with specific targets participating to the Wnt/βcatenin signaling.…”

Polyphenols as Potent Epigenetics Agents for Cancer

“…Tae et al found that kaempferol activates autophagy via the inhibition of G9a [ 94 ]. According to this study, kaempferol activates IRE1-JNK-CHOP signaling from the cytosol to the nucleus and inhibiting G9a triggers autophagy [ 95 , 96 , 97 , 98 , 99 , 100 , 101 ] ( Figure 1 ).…”

Induction of Apoptosis by Metabolites of Rhei Radix et Rhizoma (Da Huang): A Review of the Potential Mechanism in Hepatocellular Carcinoma

“…MALAT1 was down-regulated in both GA-treated HCC cells, and overexpression of MALAT1 partially reversed GA-induced inhibitory proliferation and metastasis, and successfully eliminated the inhibition of Wnt/ β-catenin signaling. These results suggest that the potential mechanism of GA promoting HCC apoptosis may be related to the inhibition of lncRNA Malat1-Wnt/β-catenin signaling axis (Shi et al, 2021). Methyl gallate (MG), a metabolite of GA, can also induce apoptosis of HCC cell lines, which is associated with activation of caspase-3 and regulation of Bcl2, Bax and Bad ligand levels (C.Y.…”