Abstract
DNA-damaging agents have been used in cancer chemotherapy for a long history. Unfortunately, chemotherapeutic treatment strategies against hepatocellular carcinoma (HCC) are still ineffective. We screened a novel DNA-damaging compound, designated as 0404, by using time-dependent cellular response profiling (TCRP) based on unique DNA-damage characteristics. We used human HCC cell lines and HCC xenograft mouse model to analyze the anti-cancer effects of 0404. Transcriptome and miRNA arrays were used to verify the anti-cancer mechanism of 0404. It was confirmed that p53 signaling pathway was crucial in 0404 anti-cancer activity and the expression of miR-34a, a key tumor-suppressive miRNA, was up-regulated in 0404-treated HepG2 cells. MiR-34a expression was also down-regulated in HCCs compared with corresponding non-cancerous hepatic tissues. We further identified the mechanisms of 0404 in HepG2 cells. 0404 increased miR-34a expression and acylation p53 protein levels and decreased SIRT1 protein levels in a concentration-dependent manner. The sensitivity of HepG2 cells to 0404 was significantly decreased by transfection with miR-34a inhibitors and SIRT1 protein levels were up-regulated by miR-34a inhibition. Our findings show that 0404 is probably an attractive agent for treating HCC, especially in HCC with wide type (WT) p53, through forming a p53/miR-34a/SIRT1 signal feedback loop to promote cell apoptosis.
Highlights
Hepatocellular carcinoma, a common malignant tumor, is recognised as the third most common cause for cancer-related mortality[1, 2] due to a lack of effective treatment options
We studied the expression of miR-34a and acetylated p53 (Ac-p53) in five hepatocellular carcinoma (HCC) tissues and the adjacent non-cancerous liver tissues (Fig. 5A)
We further explored whether miR-34a was involved in p53-mediated anti-cancer effect of 0404
Summary
0404 is screened as a DNA-damaging compound using TCRP. Using the TCRP approach based on a unique DNA-damaging TCRP signature[9], we have screened as a novel DNA-damaging compound, designated as 0404. Compared with the classical DNA-damaging agent (e.g. Nutlin-3 and 5-FU), 0404 induced significant growth inhibition in H292 cells at a nM concentration (Fig. 1A). Compared to the vehicle group, significant growth retardation was induced by 4 μmol/kg 0404 at day 25, indicating 0404 was an effective anti-HCC agent in vivo. What’s more, p53 level was up-regulated in the HepG2 tumors excised from nude mice after treatment with 0404 (Fig. 3D). This validated that p53 played a crucial part in the anti-cancer effects of 0404 in vivo. 0404 may inhibit HCC growth by forming a p53/miR34a/SIRT1/Ac-p53 positive feedback loop
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