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miR-942 decreases TRAIL-induced apoptosis through ISG12a downregulation and is regulated by AKT

Nianli Liu1, Chaohui Zuo2, Xiaohong Wang3

  • 1Research Center of Cancer Prevention & Treatment, Translational Medicine Research Center of Liver Cancer, Hunan Provincial Tumor Hospital (Affiliated Tumor Hospital of Xiangya Medical School of Central South University), Changsha, China. Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China.

Oncotarget
|June 28, 2014
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in cancer is linked to decreased interferon stimulated gene 12a (ISG12a). MicroRNA-942 (miR-942) drives this resistance by downregulating ISG12a, impacting cancer cell survival and TRAIL therapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy agent.
  • Many cancer cells exhibit resistance to TRAIL-induced apoptosis, with underlying mechanisms often unclear.
  • Understanding TRAIL resistance is crucial for developing effective targeted cancer treatments.

Purpose of the Study:

  • To elucidate the molecular mechanisms of TRAIL resistance in hepatocellular carcinoma (HCC) and gastric cancer cells.
  • To investigate the role of interferon stimulated gene 12a (ISG12a) and microRNA-942 (miR-942) in TRAIL resistance.
  • To explore the potential of miR-942 as a therapeutic marker for TRAIL-resistant tumors.

Main Methods:

  • Utilized molecular biological and immunological techniques to study TRAIL-resistant cancer cells.
  • Conducted in vivo experiments using human liver cancer xenografts in mice to assess ISG12a function.
  • Analyzed the correlation between miR-942 and ISG12a expression in cancer cells and tissues.
  • Manipulated miR-942 and ISG12a levels to determine their impact on TRAIL sensitivity.

Main Results:

  • ISG12a expression was found to be decreased in TRAIL-resistant cancer cells.
  • ISG12a was identified as a regulator of cancer cell sensitivity to TRAIL, both in vitro and in vivo.
  • A significant inverse correlation was observed between miR-942 expression and ISG12a levels.
  • Overexpression of miR-942 in TRAIL-sensitive cells led to reduced ISG12a and induced TRAIL resistance.
  • Knockdown of miR-942 in TRAIL-resistant cells restored ISG12a expression and sensitized cells to TRAIL.
  • The AKT pathway was implicated in mediating TRAIL resistance through miR-942's downregulation of ISG12a.

Conclusions:

  • Downregulation of ISG12a by miR-942 is a key mechanism maintaining TRAIL resistance and promoting cancer cell survival.
  • MiR-942 plays a critical role in the development and maintenance of TRAIL resistance in HCC and gastric cancer.
  • MiR-942 represents a potential novel drug response marker for designing therapeutics against TRAIL-resistant tumors.

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