PMID- 31863486
OWN - NLM
STAT- MEDLINE
DCOM- 20210429
LR  - 20210429
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 72
IP  - 3
DP  - 2020 Sep
TI  - MRP3-Mediated Chemoresistance in Cholangiocarcinoma: Target for 
      Chemosensitization Through Restoring SOX17 Expression.
PG  - 949-964
LID - 10.1002/hep.31088 [doi]
AB  - BACKGROUND AND AIMS: A limitation for the treatment of unresectable 
      cholangiocarcinoma (CCA) is its poor response to chemotherapy, which is partly 
      due to reduction of intracellular levels of anticancer drugs through ATP-binding 
      cassette (ABC) pumps. Low expression of SOX17 (SRY-box containing gene 17), a 
      transcription factor that promotes biliary differentiation and phenotype 
      maintenance, has been associated with cholangiocyte malignant transformation. 
      Whether SOX17 is also involved in CCA chemoresistance is investigated in this 
      study. APPROACH AND RESULTS: SOX17 expression in human CCA cells (EGI-1 and 
      TFK-1) selectively potentiated cytotoxicity of SN-38, 5-fluorouracil and 
      mitoxantrone, but not that of gemcitabine, capecitabine, cisplatin, or 
      oxaliplatin. The analysis of the resistome by TaqMan low-density arrays revealed 
      changes affecting primarily ABC pump expression. Single-gene quantitative 
      real-time PCR, immunoblot, and immunofluorescence analyses confirmed that MRP3 
      (multidrug resistance associated protein 3), which was highly expressed in CCA 
      human tumors, was down-regulated in SOX17-transduced CCA cells. The substrate 
      specificity of this pump matched that of SOX17-induced in vitro selective 
      chemosensitization. Functional studies showed lower ability of SOX17-expressing 
      CCA cells to extrude specific MRP3 substrates. Reporter assay of MRP3 promoter 
      (ABCC3pr) revealed that ABCC3pr activity was inhibited by SOX17 expression and 
      SOX2/SOX9 silencing. The latter was highly expressed in CCA. Moreover, SOX2/9, 
      but not SOX17, induced altered electrophoretic mobility of ABCC3pr, which was 
      prevented by SOX17. The growth of CCA tumors subcutaneously implanted into 
      immunodeficient mice was inhibited by 5-fluorouracil. This effect was enhanced by 
      co-treatment with adenoviral vectors encoding SOX17. CONCLUSIONS: SOX9/2/17 are 
      involved in MRP3-mediated CCA chemoresistance. Restored SOX17 expression, in 
      addition to its tumor suppression effect, induces selective chemosensitization 
      due to MRP3 down-regulation and subsequent intracellular drug accumulation.
CI  - (c) 2020 by the American Association for the Study of Liver Diseases.
FAU - Lozano, Elisa
AU  - Lozano E
AD  - Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, 
      Salamanca, Spain.
AD  - National Institute for the Study of Liver and Gastrointestinal Diseases, Carlos 
      III National Health Institute, Madrid, Spain.
FAU - Asensio, Maitane
AU  - Asensio M
AD  - Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, 
      Salamanca, Spain.
FAU - Perez-Silva, Laura
AU  - Perez-Silva L
AD  - Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, 
      Salamanca, Spain.
FAU - Banales, Jesus M
AU  - Banales JM
AD  - National Institute for the Study of Liver and Gastrointestinal Diseases, Carlos 
      III National Health Institute, Madrid, Spain.
AD  - Department of Hepatology and Gastroenterology, Biodonostia Health Research 
      Institute, Donostia University Hospital, University of the Basque Country, San 
      Sebastian, Spain.
AD  - Ikerbasque, Bilbao, Spain.
FAU - Briz, Oscar
AU  - Briz O
AD  - Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, 
      Salamanca, Spain.
AD  - National Institute for the Study of Liver and Gastrointestinal Diseases, Carlos 
      III National Health Institute, Madrid, Spain.
FAU - Marin, Jose J G
AU  - Marin JJG
AUID- ORCID: 0000-0003-1186-6849
AD  - Experimental Hepatology and Drug Targeting, IBSAL, University of Salamanca, 
      Salamanca, Spain.
AD  - National Institute for the Study of Liver and Gastrointestinal Diseases, Carlos 
      III National Health Institute, Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200711
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HMGB Proteins)
RN  - 0 (Multidrug Resistance-Associated Proteins)
RN  - 0 (SOX17 protein, human)
RN  - 0 (SOX9 Transcription Factor)
RN  - 0 (SOXB1 Transcription Factors)
RN  - 0 (SOXF Transcription Factors)
RN  - 0 (Sox17 protein, mouse)
RN  - 1YV0492L5Z (multidrug resistance-associated protein 3)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - *Bile Duct Neoplasms/drug therapy/metabolism/pathology
MH  - Cell Line, Tumor
MH  - *Cholangiocarcinoma/drug therapy/metabolism/pathology
MH  - Down-Regulation
MH  - Drug Resistance, Neoplasm
MH  - Gene Expression Regulation, Neoplastic
MH  - HMGB Proteins/*metabolism
MH  - Humans
MH  - Mice
MH  - Multidrug Resistance-Associated Proteins/*metabolism
MH  - SOX9 Transcription Factor/*metabolism
MH  - SOXB1 Transcription Factors/*metabolism
MH  - SOXF Transcription Factors/*metabolism
MH  - Xenograft Model Antitumor Assays
EDAT- 2019/12/22 06:00
MHDA- 2021/04/30 06:00
CRDT- 2019/12/22 06:00
PHST- 2019/05/31 00:00 [received]
PHST- 2019/12/10 00:00 [accepted]
PHST- 2019/12/22 06:00 [pubmed]
PHST- 2021/04/30 06:00 [medline]
PHST- 2019/12/22 06:00 [entrez]
AID - 10.1002/hep.31088 [doi]
PST - ppublish
SO  - Hepatology. 2020 Sep;72(3):949-964. doi: 10.1002/hep.31088. Epub 2020 Jul 11.