title: Aberrantly regulated dysadherin and B-cell lymphoma 2/B-cell lymphoma 2-associated X enhances tumorigenesis and DNA targeting drug resistance of liver cancer stem cells.
abstract: Cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) are frequently resistant to current therapeutic regimens and therefore responsible for tumor recurrence. Previous studies have reported that expression levels of dysadherin in CSCs may be used as a prognostic indicator, which is also responsible for treatment failure and poor survival rates. The present study analyzed the association of enhanced dysadherin levels with drug resistance and evasion of apoptosis in human HCC SP cells. An SP of 3.7% was isolated from human HCC cells using fluorescence‑activated cell sorting. These SP cells displayed elevated levels of dysadherin and stemness proteins as well as high resistance to chemotherapeutic drugs and apoptosis. In order to reveal the possible link between dysadherin levels and tumorigenesis of SP cells, small interfering RNA technology was used to knockdown the expression of dysadherin in SP cells. Of note, the siRNA‑transfected SP cells showed significantly reduced levels of stemness proteins, and were more sensitive to DNA‑targeting drugs and apoptotic cell death as compared to non‑transfected cells. Furthermore, in vivo experiments in NON/SCID mice indicated that dysadherin‑expressing SP cells were highly tumorigenic, as they were able to induce tumor growth. The SP cell‑derived tumor tissues in turn showed elevated dysadherin levels. The results of the present study therefore suggested that knockdown of dysadherin suppressed the tumorigenic properties of cancer stem-like SP cells. Hence, dysadherin is a valuable potential target for the development of novel anti-cancer drugs.
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China.
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Zhang
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China.
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Zeng
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China.
authors.forename: Bin-Sheng
authors.initials: BS
authors.lastname: Fu
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Yi
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D007473:Ion Channels; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; C000595707:BCL2 protein, human; C451410:FXYD5 protein, human; D007473:Ion Channels; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein