Regulation of ATP-binding cassette subfamily B member 1 by Snail contributes to chemoresistance in colorectal cancer.
ATP Binding Cassette Transporter, Subfamily B
/ genetics
Cell Line
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
/ genetics
Epithelial-Mesenchymal Transition
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
HCT116 Cells
HEK293 Cells
HT29 Cells
Humans
Signal Transduction
/ genetics
Snail Family Transcription Factors
/ genetics
Up-Regulation
/ genetics
ABCB1
EMT
Snail
chemoresistance
colorectal cancer
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Jan 2020
Jan 2020
Historique:
received:
29
05
2019
revised:
15
10
2019
accepted:
31
10
2019
pubmed:
28
11
2019
medline:
14
1
2020
entrez:
28
11
2019
Statut:
ppublish
Résumé
Although accumulating evidence has indicated the intimate association between epithelial-mesenchymal transition (EMT) and acquired resistance to chemotherapy for colorectal cancer (CRC), the underlying mechanisms remain elusive. Herein, we reported that Snail, a crucial EMT controller, was upregulated in CRC tissues. Colorectal cancer cells overexpressing Snail were found to be more resistant to 5-fluorouracil (5-Fu). Mechanistic studies reveal that Snail could increase the expression of ATP-binding cassette subfamily B member 1 (ABCB1) rather than the other 23 chemoresistance-related genes. Additionally, knockdown of ABCB1 significantly attenuated Snail-induced 5-Fu resistance in CRC cells. Oxaliplatin increased Snail and ABCB1 expression in CRC cells. Snail and ABCB1 were upregulated in 5-Fu-resistant HCT-8 (HCT-8/5-Fu) cells and inhibition of Snail decreased ABCB1 in HCT-8/5-Fu cells. These results confirm the vital role played by ABCB1 in Snail-induced chemoresistance. Further investigation into the relevant molecular mechanism revealed Snail-mediated ABCB1 upregulation was independent of β-catenin, STAT3, PXR, CAR and Foxo3a, which are commonly involved in modulating ABCB1 transcription. Instead, Snail upregulated ABCB1 transcription by directly binding to its promoter. Clinical analysis confirms that increased Snail expression correlated significantly with tumor size (P = .018), lymph node metastasis (P = .033), distant metastasis (P = .025), clinical stage grade (P = .024), and poor prognosis (P = .045) of CRC patients. Moreover, coexpression of Snail and ABCB1 was observed in CRC patients. Our study revealed that direct regulation of ABCB1 by Snail was critical for conferring chemoresistance in CRC cells. These findings unraveled the mechanisms underlying the association between EMT and chemoresistance, and provided potential targets for CRC clinical treatment.
Identifiants
pubmed: 31774615
doi: 10.1111/cas.14253
pmc: PMC6942434
doi:
Substances chimiques
ABCB1 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
SNAI1 protein, human
0
Snail Family Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
84-97Subventions
Organisme : National Natural Science Foundation of China
ID : 81502599
Organisme : Natural Science Foundation of Anhui Province
ID : 1608085QH217
Organisme : China Postdoctoral Science Foundation
ID : 2016M592040
Organisme : Anhui Province Postdoctoral Science Foundation
ID : 2016B142
Organisme : Key Projects of Natural Science Research of Anhui University of Chinese Medicine
ID : 2017zrzd012
Organisme : Hunan Young Talent, China
ID : 2017RS3051
Informations de copyright
© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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