ASPP2 suppresses stem cell-like characteristics and chemoresistance by inhibiting the Src/FAK/Snail axis in hepatocellular carcinoma
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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.
KeywordsASPP2 Src Stemness Snail Drug resistance
Gene set enrichment analyses
Kyoto Encyclopedia of Genes and Genomes
Quantitative reverse-transcription polymerase chain reaction
Short hairpin RNA
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
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
- 6.Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 2009;27(9):2059–68.CrossRefPubMedGoogle Scholar
- 12.Zhao J, Wu G, Bu F, Lu B, Liang A, Cao L, et al. Epigenetic silence of ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein 1 (ASPP1) and ASPP2 genes promotes tumor growth in hepatitis B virus-positive hepatocellular carcinoma. Hepatology. 2010;51(1):142–53.CrossRefPubMedGoogle Scholar