Identification of Ror2 as a hypoxia-inducible factor target in von Hippel-Lindau-associated renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Ror2, an orphan receptor tyrosine kinase, is aberrantly expressed in various cancers, including renal cell carcinoma (RCC), contributing to invasive phenotypes.
• The regulatory role and mechanism of Ror2 in cancer remain largely undefined.
• The von Hippel-Lindau (VHL) pathway, commonly mutated in RCC, leads to hypoxia-inducible factor (HIF) stabilization and gene activation.

Purpose of the Study:

• To investigate the regulatory role of Ror2 within the VHL-HIF pathway in renal cell carcinoma.
• To elucidate the mechanism by which Ror2 is regulated in the context of VHL loss and HIF stabilization.

Main Methods:

• Analysis of Ror2 association with pVHL loss and VHL somatic mutations in RCC.
• Knockdown and rescue experiments to assess the dependence of Ror2 on HIF-1alpha and HIF-2alpha.
• Evaluation of the ROR2 promoter activity and localization of HIF-2alpha and its dimerization partner.

Main Results:

• Ror2 expression is associated with pVHL loss and VHL mutations in RCC.
• Ror2 expression is dependent on the pathological stabilization of HIF-1alpha or HIF-2alpha.
• HIF-2alpha and aryl hydrocarbon nuclear transferase bind to the ROR2 promoter via a cryptic transcriptional element.

Conclusions:

• Ror2 is uniquely regulated by the VHL-HIF axis in renal cell carcinoma.
• This regulatory mechanism involving HIF-2alpha presents a potential therapeutic target for RCC and other cancers.
• Understanding Ror2's role in the VHL-HIF pathway offers insights into cancer development and progression.