Background: Long non-coding RNAs (lncRNAs) are larger than 200 nucleotides in length and pervasively expressed across the genome. An increasing number of studies indicate that lncRNA transcripts play integral regulatory roles in cellular growth, division, differentiation and apoptosis. Deregulated lncRNAs have been observed in a variety of human cancers, including hepatocellular carcinoma (HCC). However, small sample sizes in previous studies limited statistical power to identify reliable lncRNA biomarkers associated with hepatocarcinogenesis. The potential impacts of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on expression of lncRNAs are also unclear.
MATERIALS & METHODS: In this study approved by the Institutional Review Board of Columbia University Medical Center, 65 paired HCC tumor and adjacent non-tumor tissues were collected by the Center for Liver Disease and Transplantation of the Herbert Irving Comprehensive Cancer Center. We determined the expression profiles of 90 lncRNAs, 5 housekeeping gene reference controls and one negative control using the LncProfiler™ lncRNA qPCR array (System Biosciences).
RESULTS: We found that eight lncRNAs (L1PA16, lincRNA-VLDLR, LUST, Zeb2NAT, MEG9, ncR-uPAR, p53 mRNA and TEA ncRNAs family) were significantly down-regulated in HCC tumor compared to non-tumor tissues. The fold changes ranged from -2.2 to -5.9. Four lncRNAs (H19, HOTAIR, HULC and MALAT1) previously associated with HCC were also up-regulated in tumor tissue, but did not reach statistical significance. We observed over 83% of the tumor tissues carrying one of those aberrant lncRNAs, indicating the importance of lncRNAs in HCC. Categorized by hepatitis infection, we observed that five lncRNAs were significantly repressed in HBV positive/HCV negative tumors (N = 13 pairs). No significantly aberrant lncRNA was observed in HCV positive/HBV negative tumors (N = 19) in comparison with non-tumor tissues. Within non-tumor tissues, we found 3 up-regulated lncRNAs (Kcnq1ot1, PSF inhibiting RNA and NRON) were significantly associated with HBV infection, and upregulated PRINS was significantly associated with HCV infection in comparison with viral negative cases. These data suggest that the deregulated lncRNAs found within HCC non-tumor tissues may be specifically modified by relevant hepatitis viral infection.
CONCLUSIONS: Aberrant lncRNAs are potential HCC tumor biomarkers that are impacted by HBV or HCV infection. Further investigation of tumor specific biomarkers should consider the effects of different etiologies that will improve early detection of HCC.
Citation Format: Jing Shen, Abby B. Siegel, Helen Remotti, Qiao Wang, Yueyue Shen, Regina M. Santella. Deregulated long non-coding RNAs in hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3818. doi:10.1158/1538-7445.AM2015-3818