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Anti-Cancer Agents in Medicinal Chemistry

Author(s): Jianting Long, Zhijia Yao, Yi Sui and Shi Fang*

DOI: 10.2174/1871520621666210401105344

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SphK1 Promotes Cancer Progression through Activating JAK/STAT Pathway and Up-Regulating S1PR1 Expression in Colon Cancer Cells

Page: [254 - 260] Pages: 7

  • * (Excluding Mailing and Handling)

Abstract

Background: SphK1 is a conserved lipid kinase, which can catalyze the formation of tumorpromoting factor sphingosine phosphate-1 (S1P).

Objective: This study aimed to investigate the effect of SphK1 on the proliferation/migration of colon cancer cells and associated mechanisms.

Methods: Transcription of the SphK1 gene in colon cancer cells was detected. Gene transcription of SphK1 was inhibited by transfecting with the si-SphK1 gene in colon cancer cells. Effects of SphK1 inhibition (si-SphK1) on cell migration/proliferation were detected using the transwell system and MTS. Gene transcription of SIP, S1PR1, S1PR2, S1PR3, and activation of JAK/STAT3 pathway were examined using RT-PCR and western blot assay. S1PR1 over-expressing plasmid was constructed and transfected into cells. Effects of S1PR1 overexpression on migration/proliferation of si-SphK1 transfected colon cancer cells and activation of JAK/STAT3 pathway were determined using RT-PCR and western blotting.

Results: Gene transcription of SphK1 in SW480 and HT-29 colon cancer cells was significantly inhibited by transfection of the si-SphK1 gene. Transwell migration and MTS findings showed that si-SphK1 transfection (si- SphK1 group) could reduce migration quantity and cell viability of colon cancer cells compared to the negative control (NC) (p<0.0001). SphK1 inhibition (si-SphK1 group) significantly down-regulated S1PR1 and S1PR3 gene transcription in SW480 and HT-29 cells (p<0.0001) and decreased activation level of JAKSTAT3 signaling pathway compared to NC group (p<0.05). Over-expression of S1PR1 reversed inhibitory effects of si-SphK1 on migration/proliferation of SW480 and activation of JAK/Stat3.

Conclusion: SphK1 promoted proliferation and migration of colon cancer cells through promoting JAK/STAT activation and up-regulating S1PR1 expression.

Keywords: SphK1, proliferation, colon cancer, JAK/STAT3 pathway, S1PR1, upregulation.

Graphical Abstract

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