miR-221 overexpression contributes to liver tumorigenesis

Abstract

MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most upregulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.hepatocarcinogenesis | microRNA | antagomiRs | mouse model | DDIT4

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…Paradoxically, miR-222 was previously regarded as oncogene in some reports because it could enhance some tumour cell growth by targeting CDK inhibitor p27 in vitro, and was found to be upregulated in HCC and some other types of cancers 42,51,52 ; however, its tumourpromoting role was rarely validated in vivo. Our data support miR-222 to be a tumour suppressor in HCC by controlling the stemness and tumorigenicity of a2d1 þ TICs, further confirming that the roles of miRNAs are cell context-dependent 50 .…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…The authors concluded that this miRNA is responsible for the prognosis of HCC and reduced time to recurrence. Pineau et al (2010) indicate miR-221 as a tumor growth inducer of murine liver progenitor cells through the stimulation of DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR. The overexpression of miR-221 also leads to a decreased expression of p27 (Kip1), a cell cycle inhibitor both being associated with the tumor stage and the presence of metastases (Fu et al, 2011).…”

Suppression of microRNA-96 expression inhibits the invasion of hepatocellular carcinoma cells

“…Therefore, these data suggest that miR-96 is a potential candidate target for inhibiting HCC invasion and metastasis with miRNA-based cancer therapeutics. Increased miR-96 expression has been reported in certain cancers, including chronic myeloid leukemia (19), breast (6), colorectal (5) and HCC (9). miR-96 is one of the most significantly deregulated miRNAs in colorectal cancer, and the miRNA expression profile could have relevance to the biological and clinical behavior of this disease (5).…”

“…Regarding HCC, with quantitative RT-PCR to detect miRNA expression in benign and malignant hepatocellular tumors, miR-96 was found to be overexpressed in HBV-associated HCC (7). Recently, Pineau et al (9) found that a set of 12 miRNAs, including miR-96, are linked to disease progression from cirrhosis to HCC. These findings suggest that miR-96 plays a crucial role in HCC progression and that modulating miR-96 expression may be a new modality for cancer therapy.…”