LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in Hepatocellular Carcinoma

Cell Physiol Biochem. 2017;43(5):1926-1938. doi: 10.1159/000484116. Epub 2017 Oct 20.


Background/aims: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death. Critical roles for long non-coding RNAs (lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma. However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have not been extensively characterized.

Methods: In the current study, we have identified a HCC-expressed lncRNA termed as HANR (HCC associated long non-coding RNA). We identified HANR by microarray analysis and validated its up-regulated expression by quantitative PCR. RNA pull-down and pathway analyses were conducted to evaluate physical and functional interactions with HANR. In vivo experiments were performed to assess tumorigenesis and increase of chemoresistance. In addition, the HANR expression in HCC specimens was detected by FISH. Xenograft and orthotopic mice model was constructed to observe the effect of HANR on tumorigenesis and chemoresistance in vivo.

Results: HANR was demonstrated to be up-regulated in HCC patients and HCC cell lines. Increased HANR expression in HCC predicted short survival of patients. Knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin, while over-expression of HANR showed the opposite effects. It was found that HANR bind to GSKIP for regulating the phosphorylation of GSK3β in HCC.

Conclusion: Our results demonstrate that HANR contributes to the development of HCC and is a promising therapeutic target for chemosensitization of HCC cells to doxorubicin, which may represent a promising therapeutic target in the future.

Keywords: Chemoresistance; GSK3β; GSKIP; Hepatocellular carcinoma; Long non-coding RNA; Tumorigenesis.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Blotting, Western
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Cell Transformation, Neoplastic / genetics
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • In Situ Nick-End Labeling
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Nude
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / physiology*
  • Topoisomerase II Inhibitors / pharmacology


  • RNA, Long Noncoding
  • Topoisomerase II Inhibitors
  • Doxorubicin