Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Proliferation
Colorectal Neoplasms
/ drug therapy
Disease Progression
Drug Resistance, Neoplasm
Fluorouracil
/ administration & dosage
Gene Expression Regulation, Neoplastic
Humans
Hyaluronan Receptors
/ genetics
Mice
Mice, Nude
Mucin 5AC
/ genetics
Oxaliplatin
/ administration & dosage
Prognosis
Survival Rate
Tumor Cells, Cultured
Wnt Signaling Pathway
Xenograft Model Antitumor Assays
beta Catenin
/ genetics
5′-fluorouracil
CD44
Chemoresistance
Colon cancer
Colorectal cancer
MUC5AC
Mucins
β-Catenin
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
25 02 2020
25 02 2020
Historique:
received:
02
10
2019
accepted:
13
02
2020
entrez:
27
2
2020
pubmed:
27
2
2020
medline:
2
2
2021
Statut:
epublish
Résumé
Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). In normal physiological conditions, secretory mucin MUC5AC is not expressed in the colonic mucosa, whereas its aberrant expression is observed during development of colon cancer and its precursor lesions. To date, the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure. MUC5AC expression was determined in colon tissue microarray by immunohistochemistry. A RNA interference and CRISPR/Cas9-mediated system was used to knockdown/knockout the MUC5AC in CRC cell lines to delineate its role in CRC tumorigenesis using in vitro functional assays and in vivo (sub-cutaneous and colon orthotopic) mouse models. Finally, CRC cell lines and xenograft models were used to identify the mechanism of action of MUC5AC. Overexpression of MUC5AC is observed in CRC patient tissues and cell lines. MUC5AC expression resulted in enhanced cell invasion and migration, and decreased apoptosis of CRC cells. MUC5AC interacted with CD44 physically, which was accompanied by the activation of Src signaling. Further, the presence of MUC5AC resulted in enhanced tumorigenesis and appearance of metastatic lesions in orthotopic mouse model. Additionally, up-regulation of MUC5AC resulted in resistance to 5-fluorouracil (5-FU) and oxaliplatin, and its knockout increased sensitivity to these drugs. Finally, we observed that up-regulation of MUC5AC conferred resistance to 5-FU through down-regulation of p53 and its target gene p21 and up-regulation of β-catenin and its target genes CD44 and Lgr5. Our findings suggest that differential expression of secretory mucin MUC5AC results in enhanced tumorigenesis and also confers chemoresistance via CD44/β-catenin/p53/p21 signaling.
Sections du résumé
BACKGROUND
Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). In normal physiological conditions, secretory mucin MUC5AC is not expressed in the colonic mucosa, whereas its aberrant expression is observed during development of colon cancer and its precursor lesions. To date, the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure.
METHODS
MUC5AC expression was determined in colon tissue microarray by immunohistochemistry. A RNA interference and CRISPR/Cas9-mediated system was used to knockdown/knockout the MUC5AC in CRC cell lines to delineate its role in CRC tumorigenesis using in vitro functional assays and in vivo (sub-cutaneous and colon orthotopic) mouse models. Finally, CRC cell lines and xenograft models were used to identify the mechanism of action of MUC5AC.
RESULTS
Overexpression of MUC5AC is observed in CRC patient tissues and cell lines. MUC5AC expression resulted in enhanced cell invasion and migration, and decreased apoptosis of CRC cells. MUC5AC interacted with CD44 physically, which was accompanied by the activation of Src signaling. Further, the presence of MUC5AC resulted in enhanced tumorigenesis and appearance of metastatic lesions in orthotopic mouse model. Additionally, up-regulation of MUC5AC resulted in resistance to 5-fluorouracil (5-FU) and oxaliplatin, and its knockout increased sensitivity to these drugs. Finally, we observed that up-regulation of MUC5AC conferred resistance to 5-FU through down-regulation of p53 and its target gene p21 and up-regulation of β-catenin and its target genes CD44 and Lgr5.
CONCLUSION
Our findings suggest that differential expression of secretory mucin MUC5AC results in enhanced tumorigenesis and also confers chemoresistance via CD44/β-catenin/p53/p21 signaling.
Identifiants
pubmed: 32098629
doi: 10.1186/s12943-020-01156-y
pii: 10.1186/s12943-020-01156-y
pmc: PMC7041280
doi:
Substances chimiques
Biomarkers, Tumor
0
CD44 protein, human
0
CTNNB1 protein, human
0
Hyaluronan Receptors
0
MUC5AC protein, human
0
Mucin 5AC
0
beta Catenin
0
Oxaliplatin
04ZR38536J
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
37Subventions
Organisme : NCI NIH HHS
ID : R01 CA206444
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA200466
Pays : United States
Organisme : NCI NIH HHS
ID : R44 CA224619
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127297
Pays : United States
Organisme : NCI NIH HHS
ID : R41 CA213718
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183459
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA210637
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA217798
Pays : United States
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