Acyclic retinoid suppresses MYCN to inhibit HCC


View:412 Time:2018-04-24


A study, conducted by researchers from RIKEN Center for Life Science Technologies, Kanazawa University, Tottori University, Nagoya University, KOWA Co. Ltd, The Jikei University School of Medicine, Tokyo Medical and Dental University, Kyoto University, Gifu University, and Tottori University, has shed light on working mechanisms of the anti-cancer compound acyclic retinoid (ACR).

Liver cancer is one of the most successful killers among humans, which is responsible for hundreds of millions of deaths annually. It's estimated that the overall five-year survival rate for all stages of liver cancer is as low as 15%. Other medical conditions such as cirrhosis contribute to this low survival rate. Liver cancer can be classified into several types based on the type of cells that becomes cancerous. Of those, hepatocellular carcinoma (HCC), which develops from the main liver cells called hepatocytes, is the most common form of primary liver cancer. HCC is a fatal cancer, in part due to its high recurrence rate. It is the liver cancer stem cells that trigger recurrence.

ACR, a synthetic vitamin A-like compound, is able to prevent recurrence of HCC by inducing apoptosis in HCC cells. Previous studies have shown that ACR could prevent recurrence of HCC in patients who have had surgery to remove their primary tumors. Animal experiments also support the anti-cancer effect of ACR. At the molecular level, ACR induces both activation of caspase 3 as well as the expression and activation of TG2, which together initiate the apoptotic pathway via degrading/crosslinking and inactivation of the transcription factor, Sp1. However, understanding of the working mechanisms of ACR is far from complete.

In this work, the researchers carried out a series of experiments in HCC cell cultures, animal models, and liver biopsies obtained from HCC patients in order to identify the target of ACR. Through transcriptome analysis, they found that MYCN -- a well-recognized oncogene in neuroblastoma -- was expressed at higher levels in HCC cells than in normal liver cells, and treatment with ACR greatly inhibited MYCN expression in HCC cells. MYCN expression was positively correlated with cancer stem cell markers in human HCC. Furthermore, ACR selectively eliminated the MYCN-positive cancer stem cell subpopulation but not differentiated tumor cells.

Furthermore, the researchers also investigated a total of 12 HCC patients who received ACR treatment after surgical removal of their tumors. The patients' liver biopsies were obtained and analyzed before and after ACR treatment. Results showed that MYCN expression was reduced in some of the patients who received a higher dose of ACR, but not in those who received a lower dose. Besides, analysis of data of 371 HCC patients revealed that patients with MYCN overexpression had a worse prognosis compared with other patients.

These results indicate that MYCN could be a prognostic biomarker and therapeutic target of ACR for liver cancer stem cells in HCC. The researchers have summarized their findings in a paper titled "Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid," appearing in the journal PNAS. The study identifies MYCN as a target of the anti-cancer agent ACR and opens an avenue for development of novel drugs for HCC treatment.
 
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