Active PLK1-driven metastasis is amplified by TGF-β signaling that forms a positive feedback loop in non-small cell lung cancer.
Animals
Carcinoma, Non-Small-Cell Lung
/ genetics
Cell Cycle Proteins
/ genetics
Cell Line, Tumor
Cell Movement
Databases, Genetic
Epithelial-Mesenchymal Transition
Feedback, Physiological
Humans
Lung Neoplasms
/ genetics
Male
Mice
Mice, Inbred BALB C
Neoplasm Metastasis
Phosphorylation
Prognosis
Protein Serine-Threonine Kinases
/ genetics
Proto-Oncogene Proteins
/ genetics
Signal Transduction
Survival Rate
Transforming Growth Factor beta
/ metabolism
Xenograft Model Antitumor Assays
Polo-Like Kinase 1
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
17
04
2019
accepted:
11
09
2019
revised:
10
09
2019
pubmed:
25
9
2019
medline:
8
1
2021
entrez:
25
9
2019
Statut:
ppublish
Résumé
Early findings that PLK1 is highly expressed in cancer have driven an exploration of its functions in metastasis. However, whether PLK1 induces metastasis in vivo and its underlying mechanisms in NSCLC have not yet been determined. Here, we show that the expression of active PLK1 phosphorylated at T210, abundant in TGF-β-treated lung cells, potently induced metastasis in a tail-vein injection model. Active PLK1 with intact polo-box and ATP-binding domains accelerated cell motility and invasiveness by triggering EMT reprogramming, whereas a phosphomimetic version of p-S137-PLK1 did not, indicating that the phosphorylation status of PLK1 may determine the cell traits. Active PLK1-driven invasiveness upregulated TGF-β signaling and TSG6 encoded by TNFAIP6. Loss of TNFAIP6 disturbed the metastatic activity induced by active PLK1 or TGF-β. Clinical relevance shows that PLK1 and TNFAIP6 are strong predictors of poor survival rates in metastatic NSCLC patients. Therefore, we suggest that active PLK1 promotes metastasis by upregulating TGF-β signaling, which amplifies its metastatic properties by forming a positive feedback loop and that the PLK1/TGF-β-driven metastasis is effectively blocked by targeting PLK1 and TSG6, providing PLK1 and TSG6 as negative markers for prognostics and therapeutic targets in metastatic NSCLC.
Identifiants
pubmed: 31548612
doi: 10.1038/s41388-019-1023-z
pii: 10.1038/s41388-019-1023-z
pmc: PMC6976524
doi:
Substances chimiques
Cell Cycle Proteins
0
Proto-Oncogene Proteins
0
Transforming Growth Factor beta
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
767-785Commentaires et corrections
Type : ErratumIn
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