The Chinese Academy of Sciences’ Suzhou Institute of Biomedical Engineering and Technology recently reported that the DMDRMR/miR-378a-5p/ DAB2IP axis enhances angiogenesis and sunitinib resistance, suggesting that it could be used as a diagnostic, prognostic, and therapeutic goal for patients with clear cell renal cell carcinoma (ccRCC).
These findings complement and expand on their past work.
ccRCCs are a common kind of RCC that are known for being extremely angiogenic and vascularized. Certain essential genes, such as the Hippel-Lindau tumor suppressor gene, are frequently altered in RCC, resulting in aberrant activation of downstream proteins and signaling pathways and neovascularization, encouraging tumorigenesis, progression, and metastasis.
As a result, for patients with severe RCC, targeted angiogenesis inhibitors like sunitinib and sorafenib have been employed as first-line treatments. The majority of patients, however, gain medication resistance to the angiogenesis therapy. As a result, a better knowledge of tumor angiogenesis in ccRCC is essential.
The greatest vascular growth factor in promoting tumor angiogenesis is vascular endothelial cell growth factor A (VEGFA), a member of the VEGF family. VEGFA, which stimulates endothelial cell differentiation, proliferation, migration, and angiogenesis by attaching to its major receptor VEGFR2, is highly expressed in tumor cells. As a result, the VEGFA/VEGFR2 signaling pathways are important in tumor angiogenesis.
Last year, the scientists found that a long non-coding RNA known as DNA methylation-deregulated and RNA m6A reader-cooperating lncRNA (DMDRMR) acts as a cofactor for insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), allowing it to stabilize target genes in an m6A-dependent manner, and therefore plays important oncogenic roles in ccRCC.
They also discovered that DMDRMR enhances VEGFA expression and affects angiogenesis-related biological processes, but that these actions are autonomous of its binding protein IGF2BP3. As a result, a modern research question has arisen: does DMDRMR stimulate neovascularization in ccRCC, and if so, how?
The scientists concluded that DMDRMR acts as a miR-378a-5p sponge, increasing the expression of the enhancer of zeste homolog 2 (EZH2) and smad ubiquitination regulatory factor 1 (SMURF1), boosting EZH2-mediated transcriptional repression of DOC-2/DAB2 interactive protein (DAB2IP) and SMURF1-mediated degradation of DAB2IP.
As a result, in ccRCC, this axis triggers the VEGFA/VEGFR2 signaling pathway, promoting angiogenesis and tumor cell resistance to sunitinib.
They also discovered that the DMDRMR/miR-378a-5p/IGF2BP3 axis has high expression and a good correlation with ccRCC patients and that the combination of overexpressed DMDRMR and negatively regulated DAB2IP anticipated the poorest overall survival of ccRCC patients, implying that the axis could be a new target for ccRCC patients’ mixture diagnosis/therapy.
These findings could have many clinical implications for developing tailored therapy for patients with ccRCC in the coming years.
Zhu, Y., et al. (2022) DMDRMR promotes angiogenesis via antagonizing DAB2IP in clear cell renal cell carcinoma. Cell Death & Disease. doi.org/10.1038/s41419-022-04898-3.