Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Human adenocarcinomas frequently exhibit mutations in KRAS, MYC, and TP53.
• These genetic alterations can promote tumor angiogenesis by increasing vascular endothelial growth factor (VEGF) production.

Purpose of the Study:

• To investigate the role of microRNAs in mediating tumor vascularization and growth in the context of KRAS and MYC co-expression.
• To elucidate the molecular mechanisms by which MYC influences tumor angiogenesis beyond VEGF.

Main Methods:

• Utilized Kras-transformed mouse colonocytes, with and without p53.
• Introduced Myc-encoding retroviruses and miR-17-92 encoding retroviruses.
• Employed antisense oligoribonucleotides for microRNA knockdown.
• Assessed tumor vascularization, growth, and expression of thrombospondin-1 (Tsp1) and connective tissue growth factor (CTGF).

Main Results:

• Kras and Myc co-expression in colonocytes led to increased tumor vascularization and growth, independent of VEGF levels.
• Enhanced neovascularization correlated with decreased expression of anti-angiogenic factors Tsp1 and CTGF.
• The miR-17-92 microRNA cluster was upregulated and directly repressed Tsp1 and CTGF, promoting tumor growth.
• miR-17-92 knockdown partially restored Tsp1 and CTGF, while miR-17-92 overexpression reduced them.

Conclusions:

• Establishes a critical role for the miR-17-92 microRNA cluster in mediating non-cell-autonomous tumor phenotypes induced by MYC.
• Demonstrates that microRNAs can regulate tumor angiogenesis by modulating anti-angiogenic proteins, impacting tumor growth and vascularization.