Abstract: FR-PO240

Loss of Methylthioadenosine Phosphorylase Confers Malignant Potential in Renal Cell Carcinoma

Session Information

Category: Cell Biology

  • 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation

Authors

  • Chen, Ching-Hsien, UC Davis, Davis, California, United States
  • Kyoshi, Matthew, UC Davis, Davis, California, United States
  • Yang, David, UC Davis, Davis, California, United States
  • Don, Burl R, UC Davis, Davis, California, United States
  • Weiss, Robert H., UC Davis, Nephrology, Davis, California, United States
Background

Renal cell carcinoma (RCC) has emerged as a metabolic disease characterized by dysregulated expression of metabolic enzymes. Given that patients with metastatic RCC have an unusually poor prognosis, there is an urgent need to discover metabolic molecules useful for predicting malignant changes which will lead to RCC.

Methods

The Cancer Genome Atlas (TCGA) datasets were first analyzed to discover the potential metabolic molecules associated with RCC progression. We confirmed gene expression by immunohistochemistry, qRT-PCR and Western blots. Genetic manipulations were achieved by siRNA silencing, CRISPR and ectopic expression approaches. RCC cell invasion, migration and proliferation were determined by Boyden chamber, scratch and MTT assays. In addition, signaling pathway activity in RCC cells was assessed and compared through utilizing phospho-receptor tyrosine kinase arrays.

Results

Through an integrated two-step analysis of RCC metabolic pathways, we identified that methylthioadenosine phosphorylase (MTAP) and its substrate methylthioadenosine (MTA) are dysregulated in aggressive RCC. A decrease of MTAP expression was observed in RCC tissues and was correlated with tumor grade. We found that MTAP gene deletion was significantly associated with worse overall survival in RCC patients (n=538). Genetic manipulation of MTAP studies demonstrated that MTAP expression inhibits epithelial-mesenchymal transition, invasion and migration of RCC cells. Surprisingly, an increase of sphere-forming ability was noted in MTAP-knockout RCC cells. Loss of MTAP resulted in an activation of the IGF1R-Src-STAT3 axis in RCC cells.

Conclusion

Our results suggest a novel role of MTAP in kidney disease and contribute to a better understanding of metabolic enzymes involved in RCC oncogenesis.

Funding

  • Commercial Support