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IUBMB Life. 2018 Nov;70(11):1164-1176. doi: 10.1002/iub.1934. Epub 2018 Oct 3.

Up-regulation and tumor-promoting role of SPHK1 were attenuated by miR-330-3p in gastric cancer.

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Department of Gastroenterology, Yuhuangding Hospital of Yantai, Yantai, Shandong, China.
Department of Oncology, Yuhuangding Hospital of Yantai, Yantai, Shandong, China.


We intended to clarify the role of sphingosine kinase 1 (SPHK1) in gastric cancer (GC) using both in vitro and in vivo assays. The study was designed to identify novel therapeutic targets for GC treatment. Differential analysis was utilized to dissect two gene expression omnibus series (GSE49515 and GSE79973) microarray data form Gene Expression Omnibus (GEO) ( dataset. MRNA and protein expressions were determined by quantitative polymerase chain reaction and Western blot, respectively. GC cell growth was measured by MTT assays and verified by in vivo analysis. Cell cycle and cell apoptosis were detected via flow cytometer observation. Cell migration and invasion were assessed by wound healing assays and Transwell assays. The targeting relationship between miRNA and SPHK1/S1PR1 was identified via dual-luciferase assay. Twenty-four common differentially expressed genes were screened out from two gene expression omnibus series (GSE49515 and GSE79973), among which SPHK1 was chosen for its higher fold change. We found elevated SPHK1 expression in GC tissues and cells, along with an increased concentration of SPHK1-generated sphingosine-1-phosphate (S1P) in both GC serum and tissue. SPHK1 knockdown significantly suppressed cell proliferation, migration, and invasion of MKN1 and KATO3 cells. It also blocked cell cycle and induced apoptosis in MKN1 and KATO3 cells. Silencing of SPHK1 also refrained tumor growth and inhibited S1P level. MiR-330-3p directly targeted SPHK1 and S1PR1. Overexpressed miR-330-3p in MKN1 cells repressed SPHK1 and S1PR1 expressions like their chemical inhibitors-SPHK1 inhibitors (FTY720) and S1PR1 inhibitors (VPC23019), and acted anti-tumor both in vitro and in vivo. Our study provides evidence that SPHK1 was promotive for GC tumor growth and cell biological behaviors, and that miR-330-3p targeted 3'-UTR of SPHK1 and inhibited its expression. SPHK1 was expected to become a new molecular marker and miR-330-3p a novel therapeutic target for GC.


S1P; SPHK1; gastric cancer; miR-330-3p


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