title: ASPP2 suppresses stem cell-like characteristics and chemoresistance by inhibiting the Src/FAK/Snail axis in hepatocellular carcinoma.
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.
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing, China.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing, China.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, China.
authors.forename: Sujie
authors.initials: S
authors.lastname: Zhang
authors.affiliation: PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing, China.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yin
authors.affiliation: PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing, China.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing, China.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.affiliation: PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing, China.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Antibody Medicine and Targeting Therapy, Shanghai, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
authors.affiliation: PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing, China. zhaojian@smmu.edu.cn.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, China. zhaojian@smmu.edu.cn.|International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, New Building 9th Floor, Shanghai, China. zhaojian@smmu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; C090468:TP53BP2 protein, human; D051417:Focal Adhesion Kinase 1; D019061:src-Family Kinases
keywords: ASPP2; Drug resistance; Snail; Src; Stemness