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. 2021 Nov 12;20(1):147.
doi: 10.1186/s12943-021-01451-2.

STK3 promotes gastric carcinogenesis by activating Ras-MAPK mediated cell cycle progression and serves as an independent prognostic biomarker

Bonan Chen #  1   2   3 , Wai Nok Chan #  1   2   3 , Chun Wai Mui #  1   2   3 , Xiaoli Liu  1   2   3 , Jinglin Zhang  1   2   3 , Yifei Wang  1   2   3 , Alvin H K Cheung  1 , Aden K Y Chan  1 , Ronald C K Chan  1 , Kam Tong Leung  4 , Yujuan Dong  2 , Yi Pan  5 , Huixing Ke  6 , Li Liang  7 , Zhaocai Zhou  8 , Chi Chun Wong  2 , William K K Wu  9 , Alfred S L Cheng  10 , Jun Yu  2   11 , Kwok Wai Lo  1   3 , Ka Fai To  12   13   14 , Wei Kang  15   16   17
Affiliations

STK3 promotes gastric carcinogenesis by activating Ras-MAPK mediated cell cycle progression and serves as an independent prognostic biomarker

Bonan Chen et al. Mol Cancer. .
No abstract available

Keywords: Gastric cancer; Oncogene; Ras-MAPK signaling; STK3.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
STK3 is upregulated in GC patients (***, P < 0.001). a The STK3 genetic alterations (gene amplification, deep deletion, or somatic mutation) and mRNA expression in primary GC samples from the TCGA cohort (total alteration rate: 24%). b The positive correlation of STK3 copy-number alterations with its mRNA expression. c, d STK3 mRNA expression is upregulated in the tumor tissues compared with it in normal tissue group from TCGA and ACRG cohorts. e STK3 is upregulated in tumor samples compared with paired adjacent nontumorous samples. f The STK3 mRNA is differently expressed across five molecular subtypes in TCGA cohort. STK3 was significantly upregulated in EBV-positive and microsatellite-instable types of GC (P < 0.001). g STK3 mRNA expression is abundantly expressed in intestinal-type GCs compared with diffuse-type GCs. h The STK3 mRNA expression in four molecular subtypes proposed by ACRG cohort (P < 0.001). i The STK3 protein expression is increased in GC samples compared with the paired normal controls. j The expression of STK3 is positively correlated with cell cycle genes from TCGA cohort. k The cell cycle-related pathways are positively correlated with high STK3 expression by GSEA (P < 0.05). l STK3-related DEGs (|Fold Change| > 2, P < 0.05) were enriched in cell cycle and DNA replication through KEGG enrichment analysis (FDR < 0.001). m STK3-related DEGs were enriched in cell cycle progression through GO enrichment analysis (FDR < 0.001)
Fig. 2
Fig. 2
STK3 promotes GC by activating the Ras-MAPK signaling pathway (*, P < 0.05; **, P < 0.01; ***, P < 0.001). a The heatmap of STK family members in nine GC cell lines. STK3 is abundantly expressed, especially in NCI-N87 and MKN28 cells. b, c The STK3 mRNA and protein expression were significantly decreased after siSTK3 transfection in NCI-N87 and MKN28 cells. d STK3 knockdown suppressed GC cell proliferation. e Depletion of STK3 inhibited monolayer colony formation of the cancer cells. f, g GC cell migration and invasion abilities were impaired with the siSTK3 transfection. h, i, j, k GSEA demonstrated that the STK3 depletion was negatively correlated with cell cycle checkpoint, DNA replication, MAPK pathway, and Ras pathway. l, m In STK3-depleted cells, the DEGs (|Fold Change| > 1.5, P < 0.05) were enriched in the Ras-MAPK signaling pathway, cell cycle, and DNA replication through KEGG and GO enrichment analysis. n STK3 knockdown blocked the Ras activation in MKN28 cells. o The ERK is dephosphorylated and inactivated in the siSTK3 transfectants. p Knocking down STK3 induced G1 phase cell cycle arrest and apoptosis, which were confirmed by the downregulation of CDK4, CDK6, and p-Rb, and activation of cleaved-caspase 7 and cleaved-PARP. q STK3 depletion significantly suppressed the GC-derived organoid growth. Scale bar = 100 μm
Fig. 3
Fig. 3
STK3 promotes tumorigenesis by activating the Ras-MAPK pathway and serves as an independent prognostic biomarker. a, b STK3 was highly expressed in cancer cells, endothelial cells, and cancer associated fibroblasts. c The t-SNE plots of high and low expression populations of STK3, CDK4, and CCND2 in GC single-cell resolution. d The activities of cell cycle regulation, Ras signaling pathway, MAPK signaling pathway in GC cells. e In single-cell level, DEGs (in rows, q-value < 10− 10) between STK3 high and low expression were enriched in cell proliferation-related pathway by GO enrichment analysis. f Regulation of mitotic cell cycle was positively correlated with high expression of STK3 through GSEA from single-cell resolution (P < 0.001). g The proliferation and apoptosis biomarkers along with the functional pseudotime in GC development. STK3 was co-upregulated with proliferation biomarkers in the early state of tumor development. h Representative images of IHC staining of STK3 from GC tissue microarray. STK3 was predominantly localized in the cytoplasm of the cancer cells, while it demonstrated negative expression in the adjacent epithelium tissue. i STK3 was highly expressed in both intestinal-type and diffuse-type GC samples. j, k Overexpressed STK3 was associated with poor disease-specific survival in primary GCs (TCGA cohort, n = 375, P = 0.035; Hong Kong cohort, n = 263, P < 0.001). l, m STK3 abundance predicted poor disease-specific survival in intestinal-type GC patients (TCGA cohort, n = 164, P = 0.162; Hong Kong cohort, n = 141, P < 0.001). n, o In diffuse-type GCs, the upregulation of STK3 was associated with unfavorable clinical outcomes (TCGA cohort, n = 73, P = 0.331; Hong Kong cohort, n = 122, P < 0.001)
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