Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous and highly aggressive malignancy, for which there are no effective cures. Identification of a malignant stemlike subtype of HCC may offer patients with a dismal prognosis a potential targeted therapy using c-MET and Wnt pathway inhibitors. MicroRNAs (miRNAs) show promise as diagnostic and prognostic tools for cancer detection and stratification. Using a TRE-c-Met-driven transgenic HCC mouse model, we identified a cluster of 23 miRNAs that is encoded within the Dlk1-Gtl2 imprinted region on chromosome 12qF1 overexpressed in all of the isolated liver tumors. Interestingly, this region is conserved among mammalian species and maps to the human DLK1-DIO3 region on chromosome 14q32.2. We thus examined the expression of the DLK1-DIO3 miRNA cluster in a cohort of 97 hepatitis B virus-associated HCC patients and identified a subgroup (n = 18) of patients showing strong coordinate overexpression of miRNAs in this cluster but not in other cancer types (breast, lung, kidney, stomach, and colon) that were tested. Expression levels of imprinted gene transcripts from neighboring loci in this 14q32.2 region and from a subset of other imprinted sites were concomitantly elevated in human HCC. Interestingly, overexpression of the DLK1-DIO3 miRNA cluster was positively correlated with HCC stem cell markers (CD133, CD90, EpCAM, Nestin) and associated with a high level of serum α-fetoprotein, a conventional biomarker for liver cancer, and poor survival rate in HCC patients. In conclusion, our findings suggest that coordinate up-regulation of the DLK1-DIO3 miRNA cluster at 14q32.2 may define a novel molecular (stem cell-like) subtype of HCC associated with poor prognosis.
Highlights
Hepatocellular carcinoma (HCC)5 is the fifth leading cause of cancer deaths worldwide, and its incidence is increasing steadily in both the United States and China [1]
DIO3 genomic imprinted microRNA cluster highly enriched in mouse liver tumors representing a stemlike subtype of human HCC associated with poor prognosis in patients
Landscape of MicroRNA Expression Profiles in c-MET Mouse Liver Tumors and Human HCC Clinical Samples—As shown in Fig. 1a, the greatest miRNA expression changes occurred in the tumors, whereas the adjacent non-tumor liver tissues from tumor-bearing mice did not show any consistent miRNA expression changes relative to normal liver tissues from wildtype FVB mice. 39 miRNAs were found to be significantly (p Ͻ 0.01) down-regulated, and 42 miRNAs were up-regulated in the SEPTEMBER 2, 2011
Summary
Hepatocellular carcinoma (HCC)5 is the fifth leading cause of cancer deaths worldwide, and its incidence is increasing steadily in both the United States and China [1]. DIO3 genomic imprinted microRNA cluster highly enriched in mouse liver tumors representing a stemlike subtype of human HCC associated with poor prognosis in patients.
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