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Microvesicles mediate sorafenib resistance in liver cancer cells through attenuating p53 and enhancing FOXM1

Doulathunnisa Jaffar Ali1, Cong He2, Huantian Xu2

  • 1State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China; Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu 210096, China.

Life Sciences
|February 7, 2021
PubMed

Insights

Liver cancer cell-derived microvesicles (MVs) promote resistance to sorafenib therapy by transferring miR-25, which inhibits tumor suppressor p53 and promotes cell proliferation. These MVs are not suitable for drug delivery in liver cancer treatment.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Drug resistance in cancer presents significant therapeutic challenges.
  • The tumor microenvironment critically influences cancer progression and treatment response.
  • Microvesicles (MVs) mediate intercellular communication and regulate the tumor microenvironment, potentially contributing to drug resistance.

Purpose of the Study:

  • To investigate the role of liver cancer cell-secreted MVs in mediating sorafenib resistance in liver cancer cells (HepG2 and Huh7).
  • To elucidate the molecular mechanisms by which MVs induce sorafenib resistance in vitro and in vivo.

Main Methods:

  • Treatment of HepG2 and Huh7 cells with liver cancer cell-secreted MVs.
  • Assessment of sorafenib's anti-proliferative and apoptosis-inducing effects in vitro.
  • In vivo studies using xenograft mice models to evaluate tumor growth.
  • Analysis of molecular markers including HGF, Ras, miR-25, p53, and FOXM1.

Main Results:

  • Liver cancer cell-secreted MVs reduced sorafenib's anti-proliferative effect and inhibited apoptosis in a dose- and time-dependent manner.
  • In vivo, MVs increased tumor volume despite sorafenib treatment and elevated HGF and Ras protein expression.
  • miR-25 transferred from MVs to host cells reversed sorafenib-induced p53 expression, leading to increased FOXM1 and cell proliferation.

Conclusions:

  • Liver cancer cell-derived MVs confer sorafenib resistance in liver cancer cells.
  • The mechanism involves miR-25 transfer, suppression of p53, and activation of FOXM1, promoting cell cycle progression.
  • These findings suggest MVs are unsuitable as drug delivery vehicles for liver cancer therapy.
Keywords:
ApoptosisFOXM1HepG2Huh7MicrovesiclesSorafenib

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