NEK9, a novel effector of IL-6/STAT3, regulates metastasis of gastric cancer by targeting ARHGEF2 phosphorylation

Autor: Jiaqiang Dong, Kaichun Wu, Jiaoxia Zeng, Yi Sun, Bin Feng, Yulong Shang, Ying Han, Siyuan Tian, Na Wang, Yongzhan Nie, Guofang Lu
Rok vydání: 2021
Předmět:
STAT3 Transcription Factor
0301 basic medicine
Lung Neoplasms
RHOA
Immunoprecipitation
Mice
Nude
Medicine (miscellaneous)
Motility
Apoptosis
Metastasis
Mice
03 medical and health sciences
0302 clinical medicine
Stomach Neoplasms
Biomarkers
Tumor
Tumor Cells
Cultured
Tumor Microenvironment
medicine
Animals
Humans
NIMA-Related Kinases
Phosphorylation
Pharmacology
Toxicology and Pharmaceutics (miscellaneous)
Cell Proliferation
Inflammation
Mice
Inbred BALB C
biology
Interleukin-6
Chemistry
Kinase
Liver Neoplasms
Phosphoproteomics
medicine.disease
Xenograft Model Antitumor Assays
Gene Expression Regulation
Neoplastic
030104 developmental biology
Cancer research
biology.protein
NEK9
Gastric cancer
Chromatin immunoprecipitation
Rho Guanine Nucleotide Exchange Factors
030217 neurology & neurosurgery
Research Paper
Zdroj: Theranostics
ISSN: 1838-7640
Popis: Rationale: Inflammatory stimuli from the tumor microenvironment play important roles in cancer progression. However, the mechanism of promotion of cancer metastasis by inflammation in gastric cancer (GC) is poorly understood. Methods: The roles of NEK9 were validated via loss-of-function and gain-of-function experiments in vitro and in an animal model of metastasis. Cytoskeletal reorganization-associated molecules were detected by GST pull-down. The regulation of ARHGEF2 by NEK9 was investigated by phosphoproteomics analysis, immunoprecipitation (IP) and in vitro kinase assay. The transcriptional regulation of miR-520f-3p was studied using luciferase reporter and chromatin immunoprecipitation (ChIP). The expression of these proteins in GC tissues was examined by immunohistochemistry. Results: NEK9 directly regulates cell motility and RhoA activation in GC. The phosphorylation of ARHGEF2 by NEK9 is the key step of this process. NEK9 is a direct target of miR-520f-3p, which is transcriptionally suppressed by IL-6-mediated activation of STAT3. A decrease in miR-520f-3p leads to the amplification of IL-6/STAT3 by targeting GP130. A simultaneous elevation of the levels of NEK9, GP130 and p-STAT3 was confirmed in the lymph nodes and distant metastases. An increase in NEK9, GP130 and STAT3 is associated with reduced overall survival of GC patients. Conclusion: This study demonstrates that activation of STAT3 by IL-6 transcriptionally suppresses miR-520f-3p and diminishes the inhibitory effects of miR-520f-3p on NEK9 and GP130. An increase in GP130 enhances this signaling, and NEK9 directly influences cell motility and RhoA activation by targeting the phosphorylation of ARHGEF2. Targeting the IL-6-STAT3-NEK9 pathway may be a new strategy for GC treatment.
Databáze: OpenAIRE
Externí odkaz: