Secretory Mucin 5AC Promotes Neoplastic Progression by Augmenting KLF4-Mediated Pancreatic Cancer Cell Stemness.
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Carcinoma, Pancreatic Ductal
/ genetics
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Humans
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mucin 5AC
/ physiology
Neoplastic Stem Cells
/ metabolism
Pancreatic Neoplasms
/ genetics
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 01 2021
01 01 2021
Historique:
received:
19
04
2020
revised:
26
08
2020
accepted:
27
10
2020
pubmed:
1
11
2020
medline:
4
5
2021
entrez:
31
10
2020
Statut:
ppublish
Résumé
Secreted mucin 5AC (MUC5AC) is the most abundantly overexpressed member of the mucin family during early pancreatic intraepithelial neoplasia stage I (PanIN-I) of pancreatic cancer. To comprehend the contribution of Muc5ac in pancreatic cancer pathology, we genetically ablated it in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of pancreatic cancer development. Neoplastic onset and the PanIN lesion progression were significantly delayed in Muc5ac knockout (KrasG12D; Pdx-1 cre; Muc5ac-/-, KCM) animals with a 50% reduction in PanIN-2 and 70% reduction in PanIN-3 lesions compared with KC at 50 weeks of age. High-throughput RNA-sequencing analysis from pancreatic tissues of KCM animals revealed a significant decrease in cancer stem cell (CSC) markers Aldh1a1, Klf4, EpCAM, and CD133. Furthermore, the silencing of MUC5AC in human pancreatic cancer cells reduced their tumorigenic propensity, as indicated by a significant decline in tumor formation frequency by limiting dilution assay upon subcutaneous administration. The contribution of MUC5AC in CSC maintenance was corroborated by a significant decrease in tumor burden upon orthotopic implantation of MUC5AC-depleted pancreatic cancer cells. Mechanistically, MUC5AC potentiated oncogenic signaling through integrin αvβ5, pSrc (Y416), and pSTAT3 (Y705). Phosphorylated STAT3, in turn, upregulated Klf4 expression, thereby enriching the self-renewing CSC population. A strong positive correlation of Muc5ac with Klf4 and pSTAT3 in the PanIN lesions of KC mouse pancreas reinforces the crucial involvement of MUC5AC in bolstering the CSC-associated tumorigenic properties of Kras-induced metaplastic cells, which leads to pancreatic cancer onset and progression. SIGNIFICANCE: This study elucidates that
Identifiants
pubmed: 33127746
pii: 0008-5472.CAN-20-1293
doi: 10.1158/0008-5472.CAN-20-1293
pmc: PMC7990052
mid: NIHMS1643838
doi:
Substances chimiques
Biomarkers, Tumor
0
KLF4 protein, human
0
Klf4 protein, mouse
0
Kruppel-Like Factor 4
0
Kruppel-Like Transcription Factors
0
Muc5ac protein, mouse
0
Mucin 5AC
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
91-102Subventions
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 : R01 CA247471
Pays : United States
Organisme : NCI NIH HHS
ID : R44 CA224619
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL080396
Pays : United States
Organisme : NCI NIH HHS
ID : R41 CA213718
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183459
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130938
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA217798
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA210637
Pays : United States
Organisme : NCI NIH HHS
ID : R43 CA235984
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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