Proteomic profiling reveals CEACAM6 function in driving gallbladder cancer aggressiveness through integrin receptor, PRKCD and AKT/ERK signaling.
Humans
Cell Adhesion Molecules
/ metabolism
Gallbladder Neoplasms
/ metabolism
Animals
Proteomics
/ methods
GPI-Linked Proteins
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Mice
Cell Movement
Antigens, CD
/ metabolism
Cell Line, Tumor
Protein Kinase C-delta
/ metabolism
Cell Proliferation
Integrin beta1
/ metabolism
Cell Adhesion
Neoplasm Invasiveness
Signal Transduction
MAP Kinase Signaling System
Gene Expression Regulation, Neoplastic
Female
Male
Mice, Nude
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
28 Oct 2024
28 Oct 2024
Historique:
received:
09
04
2024
accepted:
18
10
2024
revised:
08
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the significantly most upregulated proteins in GBC. CEACAM6 overexpression has been observed in other cancer entities but the molecular function remains unclear. Our functional analyses in vitro and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer progression and metastasis by decreasing cell adhesion and promoting migration and invasion of GBC cells. Conversely, CEACAM6 knockdown abolished GBC aggressiveness by increasing cell adhesion while reducing cell migration, cell proliferation, and colony formation. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 supporting GBC cell migration. ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.
Identifiants
pubmed: 39468006
doi: 10.1038/s41419-024-07171-x
pii: 10.1038/s41419-024-07171-x
doi:
Substances chimiques
CEACAM6 protein, human
0
Cell Adhesion Molecules
0
GPI-Linked Proteins
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Antigens, CD
0
Protein Kinase C-delta
EC 2.7.11.13
Integrin beta1
0
Itgb1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
780Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 314905040
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 469332207
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 493697503
Organisme : Deutsche Krebshilfe (German Cancer Aid)
ID : 70113922
Informations de copyright
© 2024. The Author(s).
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