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Tumor Biology

, Volume 37, Issue 10, pp 13669–13677 | Cite as

ASPP2 suppresses stem cell-like characteristics and chemoresistance by inhibiting the Src/FAK/Snail axis in hepatocellular carcinoma

  • Lu Xu
  • Xin Tong
  • Sujie Zhang
  • Fan Yin
  • Xiaoyan Li
  • Huafeng Wei
  • Cheng Li
  • Yajun Guo
  • Jian ZhaoEmail author
Original Article

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients’ prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice. An expression profiling assay revealed that ASPP2 specifically repressed focal adhesion kinase (FAK)/Src/extracellular signal regulated kinase (ERK) signaling. ASPP2 does this by physically interacting with C-terminal Src kinase (CSK) and stimulating its kinase activity, which eventually leads to activator protein 1 (AP1)-mediated downregulation of Snail expression. In addition, pharmacologic inhibition of Src attenuated the effects of ASPP2 deficiency. Our findings present functional and mechanistic insight into the critical role of ASPP2 in the inhibition of HCC stemness and drug resistance and may provide a new strategy for therapeutic combinations to treat HCC.

Keywords

ASPP2 Src Stemness Snail Drug resistance 

Abbreviations

EMT

Epithelial-mesenchymal transition

GSEA

Gene set enrichment analyses

IF

Immunofluorescence

IP

Immunoprecipitation

KEGG

Kyoto Encyclopedia of Genes and Genomes

qRT-PCR

Quantitative reverse-transcription polymerase chain reaction

shRNA

Short hairpin RNA

SP

Side population

Notes

Acknowledgments

This work is supported in part by grants from Ministry of Science and Technology of China “973”and “863”programs (2014AA021103, 2014AA020704, 2010CB945600), National Nature Science Foundation of China (81472719, 81301781, 81402539), Beijing Municipal Commission of Science and Technology, Shanghai Key Laboratory of Cell Engineering (14DZ2272300), and Shanghai Leading Academic Discipline Project (B905).

Compliance with ethical standards

Ethical standards

The authors declare that all procedures performed in this study involving animals were approved by Institutional Animal Care and Use Committee (IACUC) of Second Military Medical University and PLA General Hospital.

Conflicts of interest

None

Supplementary material

13277_2016_5246_MOESM1_ESM.docx (33 kb)
Supplemental Methods (DOCX 33 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Lu Xu
    • 1
  • Xin Tong
    • 2
    • 3
  • Sujie Zhang
    • 2
    • 3
  • Fan Yin
    • 2
    • 3
  • Xiaoyan Li
    • 2
    • 3
  • Huafeng Wei
    • 2
    • 3
  • Cheng Li
    • 2
    • 3
  • Yajun Guo
    • 4
  • Jian Zhao
    • 2
    • 3
    • 5
    Email author
  1. 1.School of Bioscience and Bioengineering, South China University of TechnologyGuangzhouChina
  2. 2.PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of MedicineBeijingChina
  3. 3.Beijing Key Laboratory of Cell Engineering and AntibodyBeijingChina
  4. 4.State Key Laboratory of Antibody Medicine and Targeting TherapyShanghaiChina
  5. 5.International Joint Cancer InstituteThe Second Military Medical UniversityShanghaiChina

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