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FOXM1-Mediated LINC-ROR Regulates the Proliferation and Sensitivity to Sorafenib in Hepatocellular Carcinoma

Yingru Zhi1, Mubalake Abudoureyimu1, Hao Zhou2

  • 1Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.

Molecular Therapy. Nucleic Acids
|May 15, 2019
PubMed

Insights

This study reveals a new feedback loop involving LINC-ROR and FOXM1 in hepatocellular carcinoma (HCC). This loop promotes resistance to sorafenib, a key treatment for liver cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hepatocellular carcinoma (HCC) is a major global cause of cancer death.
  • Sorafenib is a vital treatment for HCC, but many patients exhibit poor response or intolerance.
  • Understanding sorafenib resistance mechanisms is crucial for improving HCC treatment outcomes.

Purpose of the Study:

  • To investigate the role of long noncoding RNAs (lncRNAs) in HCC sorafenib resistance.
  • To identify the molecular mechanisms underlying sorafenib resistance in hepatocellular carcinoma.
  • To elucidate the functional relationship between LINC-ROR, FOXM1, and sorafenib sensitivity in HCC.

Main Methods:

  • Investigated the expression of LINC-ROR in HCC cell lines.
  • Determined the transcriptional activation of LINC-ROR by FOXM1.
  • Analyzed the interaction between LINC-ROR, miR-876-5p, and FOXM1 using sponging assays.
  • Assessed the impact of LINC-ROR and FOXM1 upregulation on sorafenib sensitivity in HCC cells.
  • Performed rescue assays to validate the feedback loop's role.

Main Results:

  • LINC-ROR was found to be upregulated in HCC cell lines.
  • FOXM1 was identified as a transcriptional activator of LINC-ROR.
  • A positive-feedback loop was established where LINC-ROR sponges miR-876-5p, releasing FOXM1.
  • Upregulation of both FOXM1 and LINC-ROR significantly reduced HCC cell sensitivity to sorafenib.
  • Rescue assays confirmed the critical role of this feedback loop in sorafenib resistance.

Conclusions:

  • A novel molecular feedback loop between LINC-ROR and FOXM1 was identified in HCC.
  • This LINC-ROR/FOXM1 feedback loop plays a significant role in mediating sorafenib resistance in hepatocellular carcinoma.
  • Targeting this pathway may offer a potential therapeutic strategy for overcoming sorafenib resistance in HCC patients.
Keywords:
FOXM1HCCLINC-RORmiR-876-5psensitivitysorafenib

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