SIK2 represses AKT/GSK3β/β‐catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases |
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| Authors: | Xiao&#x;man Dai Yan&#x;hui Zhang Xiao&#x;han Lin Xiao&#x;xing Huang Yi Zhang Chao&#x;rong Xue Wan&#x;nan Chen Jian&#x;xin Ye Xin&#x;jian Lin Xu Lin |
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| Institution: | 1. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou China ; 2. Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou China ; 3. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou China |
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| Abstract: | Salt‐inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial–mesenchymal transition via inhibition of AKT/GSK3β/β‐catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3β/β‐catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.Abbreviations- AMPK
- AMP‐activated protein kinase
- Co‐IP
- co‐immunoprecipitation
- EMT
- epithelial–mesenchymal transition
- GAPDH
- glyceraldehyde‐3‐phosphate dehydrogenase
- GC
- gastric cancer
- GEO
- Gene Expression Omnibus
- H&E
- hematoxylin and eosin
- IHC
- immunohistochemistry
- mTOR
- mechanistic target of rapamycin
- NC
- negative control
- PHLPP
- PH domain leucine‐rich repeat protein phosphatase
- PP2A
- protein phosphatase 2A
- qRT‐PCR
- quantitative real‐time polymerase chain reaction
- SIK2
- salt‐inducible kinase 2
- TCF/LEF
- T cell factor/lymphoid enhancer‐binding factor
- TCGA
- The Cancer Genome Atlas
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| Keywords: | AKT/GSK3β /β ‐ catenin signaling autophagy gastric cancer protein phosphatases SIK2 |
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