Antiproliferative effect of urolithin A, the ellagic acid-derived colonic metabolite, on hepatocellular carcinoma HepG2.2.15 cells by targeting Lin28a/let-7a axis

Abstract

An abnormality in the Lin28/let-7a axis is relevant to the progression of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be a novel therapeutic target for this malignant tumor. The present study aimed to investigate the antiproliferative and anti-invasive effects of urolithin A in a stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and transwell assays. The RNA and protein expressions of targets were assessed by quantitative PCR and western blot, respectively. Results revealed that urolithin A induced cytotoxicity in HepG2.2.15 cells, which was accompanied by the cleavage of caspase-3 protein and down-regulation of Bcl-2/Bax ratio. Moreover, urolithin A suppressed the protein expressions of Sp-1, Lin28a, and Zcchc11, and elevated the expression of microRNA let-7a. Importantly, urolithin A also regulated the Lin28a/let-7a axis in transient HBx-transfected HCC HepG2 cells. Furthermore, urolithin A decelerated the HepG2.2.15 cell invasion, which was involved in suppressing the let-7a downstream factors HMGA2 and K-ras. These findings indicated that urolithin A exerted the antiproliferative effect by regulating the Lin28a/let-7a axis and may be a potential supplement for HBV-infected HCC therapy.

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“…Interestingly, in addition to being the downstream substrate of caspase-3, Bcl-2, with its antiapoptotic property, can be inactivated by caspase-3 and converted into a pro-apoptosis motivator unrelated to Bax/Bcl-2 pathway, suggesting that a feedback loop between Bcl-2 and caspase-3 exists [ 156 ]. Considerable evidence supports the idea that enhanced Bax/Bcl-2 ratio, combined with cleavage of caspase-3, takes place in various liver diseases, including chronic hepatitis, alcoholic liver, and hepatocellular carcinoma (HCC) [ 157 , 158 , 159 ].…”

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“…Among the Urolithin metabolites, Urolithin A is the major metabolite observed in humans . The health effects attributed to urolithins are numerous and diverse, ranging from antimalarial properties, free radical scavenger activity, and anti‐proliferative effects in various types of cancer in vivo and in vitro …”

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“…al. [64] the findings of the study indicated that urolithin A exerted an antiproliferative effect by regulating the Lin28a/let-7a axis and may be a potential supplement for HBV-infected HCC therapy. In the study by Liu X et al [65] the findings suggested that Stellerachamaejasme L (ESC) regressed growth and metastasis of human hepatocellular carcinoma, by downregulating microRNAs expression.…”