PMID- 31931755
OWN - NLM
STAT- MEDLINE
DCOM- 20200908
LR  - 20200908
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 20
IP  - 1
DP  - 2020 Jan 13
TI  - Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 
      signaling in hepatocellular carcinoma.
PG  - 31
LID - 10.1186/s12885-019-6480-9 [doi]
LID - 31
AB  - BACKGROUND: Chemo-resistance in hepatocellular carcinoma (HCC) is a major 
      problem, and acquired drug resistance prevents cancer therapies from achieving 
      complete responses. Molecular targeting therapy presents an opportunity to impede 
      tumor through combination or sequential therapy, while the accurate effect is 
      vague. METHODS: The efficacy of combinations between oxaliplatin and anti-cancer 
      molecular targeting drugs was screened. Strangely, the combined chemotherapy with 
      oxaliplatin and saracatinib induced significantly antagonistic effects. Then the 
      antitumor effects of combined treatment with saracatinib and oxaliplatin were 
      confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant 
      HCC. RNA sequencing was used to explore the resistance mechanism, and the roles 
      of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin 
      resistance were confirmed. RESULTS: Chemotherapy with oxaliplatin and saracatinib 
      individually induced strong anti-HCC effects, while combined or sequential 
      treatment of HCC cells with these two drugs exhibited reduced efficacy compared 
      to treatment with the single drugs. And it was saracatinib treatment caused 
      oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by 
      treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and 
      Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and 
      oxaliplatin resistance were associated with activation of Wnt signaling. 
      Interference with ABCG1 expression or inhibition of Wnt signaling resulted in 
      reversal of the saracatinib-induced oxaliplatin resistance in HCC. CONCLUSIONS: 
      These studies demonstrated that combined or sequential chemotherapy with 
      oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was 
      attributed to the activation of Wnt signaling and upregulation of ABCG1 by 
      saracatinib.
FAU - Liao, Xia
AU  - Liao X
AD  - Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, 
      Xi'an, 710061, China.
FAU - Song, Ge
AU  - Song G
AD  - Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, 
      Xi'an, 710061, China.
FAU - Xu, Zihan
AU  - Xu Z
AD  - Department of Burns and Plastic Surgery, Shaanxi Provincial People's Hospital, 
      Xi'an, 710068, China.
FAU - Bu, Yang
AU  - Bu Y
AD  - Department of Hepatobiliary Surgery, General Hospital, Ningxia Medical 
      University, Yinchuan, 750001, China.
FAU - Chang, Fan
AU  - Chang F
AD  - Metabolite Research Center, Shaanxi Institute of Microbiology, Xi'an, 710043, 
      China.
FAU - Jia, Fengan
AU  - Jia F
AD  - Metabolite Research Center, Shaanxi Institute of Microbiology, Xi'an, 710043, 
      China.
FAU - Xiao, Xuelian
AU  - Xiao X
AD  - Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong 
      University, 277 West Yanta Road, Xi'an, 710061, China.
FAU - Ren, Xuejiao
AU  - Ren X
AD  - Medical College of Yan'an University, Yan'an, 716000, China.
FAU - Zhang, Mei
AU  - Zhang M
AD  - Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong 
      University, 277 West Yanta Road, Xi'an, 710061, China.
FAU - Jia, Qingan
AU  - Jia Q
AUID- ORCID: 0000-0002-3256-7197
AD  - Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong 
      University, 277 West Yanta Road, Xi'an, 710061, China. qajia66@163.com.
LA  - eng
GR  - 81502694/National Natural Science Foundation of China/
GR  - 1191329835/Fundamental Research Funds for the Central Universities/
GR  - 2015M570330/Postdoctoral Science Foundation of China/
GR  - NZ15130/Key projects of Ningxia Natural Science Foundation/
PT  - Journal Article
DEP - 20200113
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (ABCG1 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1)
RN  - 0 (Benzodioxoles)
RN  - 0 (Quinazolines)
RN  - 0 (Wnt Proteins)
RN  - 04ZR38536J (Oxaliplatin)
RN  - 9KD24QGH76 (saracatinib)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics/*metabolism
MH  - Animals
MH  - Benzodioxoles/*pharmacology
MH  - Carcinoma, Hepatocellular/drug therapy/genetics/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Computational Biology/methods
MH  - Disease Models, Animal
MH  - Drug Antagonism
MH  - *Drug Resistance, Neoplasm
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Liver Neoplasms/drug therapy/*metabolism/pathology
MH  - Mice
MH  - Oxaliplatin/*pharmacology
MH  - Quinazolines/*pharmacology
MH  - Signal Transduction/*drug effects
MH  - Wnt Proteins/*metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC6958774
OTO - NOTNLM
OT  - ABCG1
OT  - Hepatocellular carcinoma
OT  - Oxaliplatin resistance
OT  - Saracatinib
OT  - Wnt signaling
COIS- The authors declare that they have no competing interests.
EDAT- 2020/01/15 06:00
MHDA- 2020/09/09 06:00
PMCR- 2020/01/13
CRDT- 2020/01/15 06:00
PHST- 2019/05/30 00:00 [received]
PHST- 2019/12/18 00:00 [accepted]
PHST- 2020/01/15 06:00 [entrez]
PHST- 2020/01/15 06:00 [pubmed]
PHST- 2020/09/09 06:00 [medline]
PHST- 2020/01/13 00:00 [pmc-release]
AID - 10.1186/s12885-019-6480-9 [pii]
AID - 6480 [pii]
AID - 10.1186/s12885-019-6480-9 [doi]
PST - epublish
SO  - BMC Cancer. 2020 Jan 13;20(1):31. doi: 10.1186/s12885-019-6480-9.