Related Experiment Video

Updated: Aug 13, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs

Chong Yang1, Xin Jin2,3,4, Xingchao Liu1

  • 1Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, Sichuan, China.

Cell Death & Disease
|January 20, 2023
PubMed

Insights

This study reveals TRIM15 upregulation drives tyrosine kinase inhibitor (TKI) resistance in Hepatocellular carcinoma (HCC). Targeting the AKT/FOXO1/TRIM15/LASP1 pathway may overcome TKI resistance in liver cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Systemic therapy, including tyrosine kinase inhibitors (TKIs), is standard for unresectable Hepatocellular carcinoma (HCC).
  • While TKIs improve survival, TKI resistance remains a significant clinical challenge.
  • The role of tripartite motif (TRIM) family member TRIM15 in HCC and TKI resistance is largely unknown.

Purpose of the Study:

  • To investigate the biological role of TRIM15 in Hepatocellular carcinoma (HCC) and its contribution to TKI resistance.
  • To elucidate the molecular mechanisms underlying TRIM15 upregulation and its downstream effects in TKI-treated HCC cells.

Main Methods:

  • Quantitative analysis of TRIM15 expression in TKI-treated HCC cells.
  • Investigation of the AKT/FOXO1 signaling pathway's role in regulating TRIM15.
  • Assessment of TRIM15's effect on LASP1 ubiquitination and nuclear translocation.
  • Evaluation of downstream signaling alterations, including AKT phosphorylation and Snail expression.

Main Results:

  • TRIM15 is significantly upregulated in HCC cells following TKI treatment, contributing to TKI resistance.
  • TRIM15 upregulation is mediated by the AKT/FOXO1 signaling axis.
  • TRIM15 promotes K63-linked polyubiquitination of LASP1, inducing its nuclear translocation.
  • This process modulates TKI sensitivity by increasing AKT phosphorylation and Snail expression.

Conclusions:

  • A novel AKT/FOXO1/TRIM15/LASP1 signaling loop is identified in HCC.
  • This loop plays a critical role in the development of TKI resistance.
  • Targeting this pathway presents a potential strategy for overcoming TKI resistance in Hepatocellular carcinoma.

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