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NF-κB and EGFR participate in S1PR3-mediated human renal cell carcinomas progression

Yali Yan1, Gegentuya Bao1, Jingyuan Pei1

  • 1The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, China.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|March 29, 2022
PubMed

Insights

Sphingosine 1-phosphate (S1P) promotes renal cell carcinoma (RCC) progression and metastasis by activating S1PR3. Targeting the S1P/S1PR3 axis offers a potential therapeutic strategy for RCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Sphingosine 1-phosphate (S1P) is a bioactive lipid involved in numerous physiological and pathological processes through its receptors (S1PR1-5).
  • The specific role of S1P and its receptor subtypes in renal cell carcinoma (RCC) pathogenesis remains largely unelucidated.
  • Understanding these mechanisms is crucial for identifying novel therapeutic targets in RCC.

Purpose of the Study:

  • To investigate the regulatory role of S1P in RCC progression.
  • To identify the specific receptor subtypes mediating S1P-induced effects in RCC.
  • To evaluate the S1P/S1PR3 axis as a potential therapeutic target for RCC.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) patient databases.
  • In vitro studies assessing the effects of S1P on renal cancer cell proliferation, migration, and epithelial-mesenchymal transition (EMT).
  • In vivo animal experiments to evaluate the impact of S1PR3 on RCC tumorigenesis and metastasis.
  • Mechanistic studies to elucidate signaling pathways involved in S1P/S1PR3-mediated effects.

Main Results:

  • High S1PR3 expression in RCC patients correlates with significantly worse overall survival.
  • S1P promotes renal cancer cell proliferation, migration, and EMT, with effects amplified by increased S1PR3 expression.
  • S1PR3 accelerates RCC tumorigenesis and metastasis in animal models.
  • Identified key signaling pathways: S1PR3/Gi/p38/Akt/p65/cyclin D1-CDK4 for proliferation and S1PR3/Gi/q/ERK/p38/p65 for migration.
  • S1PR3 enhances epidermal growth factor (EGF)-induced effects by increasing protein expression, not EGFR transactivation.

Conclusions:

  • The S1P/S1PR3 axis plays a significant carcinogenic role in RCC.
  • S1PR3 is a promising molecular target for developing novel small molecule therapies for S1PR3-expressing RCC.
  • Targeting S1PR3 may offer a new therapeutic avenue for patients with advanced or metastatic renal cell carcinoma.
Keywords:
EGFRNF-κBProliferationRenal cell carcinomaS1PR3Tumor metastasis

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