RNA sequencing identifies two novel liver-specific long noncoding RNAs with potential diagnostic value in hepatocellular carcinoma
Abstract
Aim: To explore the expression profiles of long noncoding RNAs (lncRNAs) and identify novel lncRNAs as biomarkers for early diagnosis and therapy of hepatocellular carcinoma (HCC). Materials & methods: Expression profiles of lncRNAs and mRNAs in five paired HCC and adjacent normal tissues were obtained by RNA sequencing. Eight lncRNAs, including two novel liver-specific lncRNAs (NONHSAT059247.2 and NONHSAT013897.2), were validated in another 74 pairs of HCC and adjacent normal tissues by quantitative reverse transcription PCR. Results: The results of quantitative reverse transcription PCR showed that NONHSAT252133.1, NONHSAT112116.2 and NONHSAT242657.1 were significantly upregulated in HCC tissues, whereas NONHSAT169790.1, NONHSAT059247.2 and NONHSAT013897.2 were significantly downregulated. Two liver-specific lncRNAs demonstrated excellent diagnostic performance: NONHSAT059247.2 (area under the curve = 0.941, 95% CI: 0.902–0.979, p < 0.0001), NONHSAT013897.2 (area under the curve = 0.944, 95% CI: 0.906–0.983, p < 0.0001). Conclusion: The liver-specific lncRNAs NONHSAT059247.2 and NONHSAT013897.2, may provide new biomarkers for the future study on diagnosis, therapy and mechanisms of HCC.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
- 2. . Epidemiology and management of hepatocellular carcinoma. Gastroenterology 156(2), 477–491 (2019).
- 3. Factors associated with delay of diagnosis of hepatocellular carcinoma in patients with cirrhosis. Clin. Gastroenterol. Hepatol.
doi:10.1016/j.cgh.2020.07.026 (2020) (Online ahead of print). • Shows that the diagnosis of hepatocellular carcinoma was delayed in a large proportion of patients with cirrhosis and explained the reasons for the delay. - 4. Long noncoding RNA TSLNC8 is a tumor suppressor that inactivates the interleukin-6/STAT3 signaling pathway. Hepatology 67(1), 171–187 (2018). • A typical study that identifies that a long noncoding RNA (lncRNA) TSLNC8 plays an important role in hepatocellular carcinoma through a mechanism of binding to a protein and regulating its function.
- 5. Long non-coding RNA UICLM promotes colorectal cancer liver metastasis by acting as a ceRNA for microRNA-215 to regulate ZEB2 expression. Theranostics 7(19), 4836–4849 (2017). • Founds that a lncRNA UICLM promoted colorectal cancer liver metastasis by a common mechanism of acting as a competing endogenous RNA.
- 6. . Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat. Rev. Gastroenterol. Hepatol. 15(3), 137–151 (2018).
- 7. . The emerging role of lncRNAs in cancer. Nat. Med. 21(11), 1253–1261 (2015). •• Emphasizes the important clinical value of tissue-specific expressed lncRNAs.
- 8. A novel, liver-specific long noncoding RNA LINC01093 suppresses HCC progression by interaction with IGF2BP1 to facilitate decay of GLI1 mRNA. Cancer Lett. 450, 98–109 (2019).
- 9. A liver-specific lncRNA, FAM99B, suppresses hepatocellular carcinoma progression through inhibition of cell proliferation, migration, and invasion. J. Cancer Res. Clin. Oncol. 145(8), 2027–2038 (2019).
- 10. LINC02499, a novel liver-specific long non-coding RNA with potential diagnostic and prognostic value, inhibits hepatocellular carcinoma cell proliferation, migration, and invasion. Hepatol. Res. 50(6), 726–740 (2020).
- 11. Diagnostic and prognostic value of lncRNA cancer susceptibility candidate 9 in hepatocellular carcinoma. World J. Gastroenterol. 25(48), 6902–6915 (2019).
- 12. . lncRNA-D16366 is a potential biomarker for diagnosis and prognosis of hepatocellular carcinoma. Med. Sci. Monit. 25, 6581–6586 (2019).
- 13. Exosomes and hepatocellular carcinoma: from bench to bedside. Int. J. Mol. Sci. 20(6), 1406 (2019).
- 14. Comprehensive analysis and experimental verification of LINC01314 as a tumor suppressor in hepatoblastoma. Biomed. Pharmacother. 98, 783–792 (2018).
- 15. Roles and regulation of long noncoding RNAs in hepatocellular carcinoma. Cancer Res. 79(20), 5131–5139 (2019).
- 16. Long noncoding RNAs: novel insights into hepatocelluar carcinoma. Cancer Lett. 344(1), 20–27 (2014).
- 17. LncRNA n335586/miR-924/CKMT1A axis contributes to cell migration and invasion in hepatocellular carcinoma cells. Cancer Lett. 429, 89–99 (2018).
- 18. LncRNA ID2-AS1 suppresses tumor metastasis by activating the HDAC8/ID2 pathway in hepatocellular carcinoma. Cancer Lett. 469, 399–409 (2020).
- 19. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell 16(4), 413–425 (2015).
- 20. lncRNA-PDPK2P promotes hepatocellular carcinoma progression through the PDK1/AKT/Caspase 3 pathway. Mol. Oncol. 13(10), 2246–2258 (2019).
- 21. microRNA-1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39-mediated PI3K/AKT/mTOR pathway in HCC. J. Cell. Mol. Med. 23(12), 8292–8304 (2019).
- 22. . Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12(8), 695–708 (2011).
- 23. . NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 4(3), 176–185 (2013).
- 24. . The NF-κB family of transcription factors and its regulation. Cold Spring Harb. Perspect. Biol. 1(4), a000034 (2009).
- 25. . NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18(5), 309–324 (2018).
- 26. . The functions and unique features of long intergenic non-coding RNA. Nat. Rev. Mol. Cell Biol. 19(3), 143–157 (2018).
- 27. LncRNA HOTAIR epigenetically suppresses miR-122 expression in hepatocellular carcinoma via DNA methylation. EBioMedicine 36, 159–170 (2018). •• Proposes the expression of lncRNAs in various tissues is more tissue-specific than the coding RNAs, implying their important role in tissues.