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MiR-125b-5p Is Involved in Sorafenib Resistance through Ataxin-1-Mediated Epithelial-Mesenchymal Transition in

Akihiro Hirao1, Yasushi Sato2, Hironori Tanaka1

  • 1Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.

Cancers
|October 13, 2021
PubMed

Insights

MicroRNA-125b-5p promotes sorafenib resistance in hepatocellular carcinoma (HCC) by suppressing ataxin-1, inducing epithelial-mesenchymal transition (EMT), and enhancing stemness, leading to poorer patient survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The mechanisms underlying sorafenib resistance in hepatocellular carcinoma (HCC) are not fully understood.
  • Identifying key molecular players is crucial for overcoming treatment resistance.

Purpose of the Study:

  • To investigate the role of microRNAs (miRNAs) in sorafenib resistance in HCC.
  • To elucidate the molecular pathways involved in miRNA-mediated resistance.

Main Methods:

  • Analysis of miRNA expression profiles in sorafenib-resistant and sensitive HCC cell lines.
  • Functional assays including drug sensitivity, migration, invasion, and epithelial-mesenchymal transition (EMT) analysis.
  • In vivo mouse models and bioinformatic analysis to identify miRNA targets and assess clinical relevance.

Main Results:

  • Four miRNAs were upregulated in resistant HCC cells; miR-125b-5p mimic transfection increased sorafenib resistance and induced EMT.
  • miR-125b-5p promoted migration, invasion, and in vivo sorafenib resistance.
  • Ataxin-1 was identified as a direct target of miR-125b-5p; its suppression led to increased resistance, EMT, and stemness.
  • Low ataxin-1 expression correlated with shorter overall survival in HCC patients.

Conclusions:

  • miR-125b-5p contributes to sorafenib resistance in HCC by targeting ataxin-1.
  • This suppression induces Snail-mediated EMT and stemness, resulting in a poor prognosis for HCC patients.
Keywords:
ataxin-1drug resistancehepatocellular carcinomamiR-125b-5psorafenib

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