RGD Reference Report - A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma. - Rat Genome Database

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A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma.

Authors: Xiao, Zhangang  Li, Chi Han  Chan, Stephen L  Xu, Feiyue  Feng, Lu  Wang, Yan  Jiang, Jian-Dong  Sung, Joseph J Y  Cheng, Christopher H K  Chen, Yangchao 
Citation: Xiao Z, etal., Cancer Res. 2014 Nov 1;74(21):6236-47. doi: 10.1158/0008-5472.CAN-14-0855. Epub 2014 Sep 12.
RGD ID: 14694835
Pubmed: PMID:25217526   (View Abstract at PubMed)
DOI: DOI:10.1158/0008-5472.CAN-14-0855   (Journal Full-text)

Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wild-type or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MIR34AHumanhepatocellular carcinoma treatmentIMP human cell line in a mouse modelRGD 
Mir34aMousehepatocellular carcinoma treatmentISOMIR34A (Homo sapiens)human cell line in a mouse modelRGD 
Mir34aRathepatocellular carcinoma treatmentISOMIR34A (Homo sapiens)human cell line in a mouse modelRGD 

Objects Annotated

Genes (Rattus norvegicus)
Mir34a  (microRNA 34a)

Genes (Mus musculus)
Mir34a  (microRNA 34a)

Genes (Homo sapiens)
MIR34A  (microRNA 34a)


Additional Information