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Targeting ROR1 inhibits glucocorticoid-induced gastric cancer growth

Rui Wang1, Quanquan Guo1, Meimei Ma2

  • 1Department of Hematology, The Second Affiliated Hospital of Soochow University, No. 1055, San Xiang Road, Gu Su District, Su Zhou City, China; Department of Oncology, The Affiliated Suqian Hospital of Xuzhou Medical University, No. 138, Huanghe Road, Su Cheng District, Suqian City, China.

Steroids
|April 17, 2023
PubMed

Insights

Dexamethasone, a glucocorticoid, promotes gastric cancer growth and metastasis by up-regulating ROR1. Blocking ROR1 inhibits tumor progression, offering a potential therapeutic strategy for gastric cancer.

Area of Science:

  • Oncology
  • Endocrinology
  • Molecular Biology

Background:

  • Glucocorticoids like dexamethasone are widely used but can paradoxically promote tumor growth and metastasis.
  • Elevated cortisol and adrenocorticotropic hormone (ACTH) levels correlate with advanced gastric cancer stages.
  • The precise mechanisms by which glucocorticoids enhance gastric cancer progression require further elucidation.

Purpose of the Study:

  • To investigate the role of dexamethasone in promoting gastric cancer growth and metastasis.
  • To elucidate the underlying molecular mechanisms involving Receptor Tyrosine Kinase Ortholog 1 (ROR1).
  • To assess the therapeutic potential of targeting ROR1 in gastric cancer.

Main Methods:

  • Quantification of serum cortisol and ACTH levels in gastric cancer patients across different stages.
  • Immunohistochemical staining to evaluate ROR1 expression in gastric cancer tissues.
  • In vitro studies on gastric cancer cell lines to assess ROR1 regulation by dexamethasone and its functional impact.
  • In vivo experiments using immunodeficient mice to evaluate the effect of ROR1 suppression on tumor growth.

Main Results:

  • Higher cortisol and ACTH levels were observed in patients with stage III/IV gastric cancer compared to stage I/II.
  • Dexamethasone treatment led to a concentration-dependent increase in ROR1 expression on gastric cancer cells.
  • High ROR1 expression in gastric tumors correlated with increased rates of relapse, metastasis, and shorter survival times.
  • ROR1 was specifically expressed on gastric cancer cells, not normal gastric epithelium.
  • In vitro and in vivo suppression of ROR1 impaired cancer cell invasion, migration, proliferation, and tumor growth.

Conclusions:

  • Dexamethasone up-regulates ROR1 expression in gastric cancer cells, contributing to tumor growth and metastasis.
  • ROR1 plays a critical role in mediating the pro-tumorigenic effects of dexamethasone in gastric cancer.
  • Targeting ROR1 represents a promising strategy to inhibit dexamethasone-induced gastric tumor progression.
Keywords:
DexamethasoneGastric cancerGlucocorticoidROR1Stress

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