A major genetic study had linked liver disease gene to bladder cancer.
The University of Colorado Cancer Center study details the discovery of a new genetic driver of bladder cancer: silencing of the gene AGL.
"We tend to think of cancer resulting from mutations that let genes make things they shouldn't or turn on when they should be quiet. But cancer can also result from loss of gene function. Some genes suppress cancer. When you turn off these suppressors, cancer grows," Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center and the study's senior author, said.
To discover which genes, when deactivated, might drive bladder cancer, Theodorescu and colleagues turned off genes, one by one, in bladder cancer cell models.
Of course, the vast majority of the genes researchers silenced made no difference - they weren't functionally related to tumor growth. But eventually in this genome-wide shRNA screen, Theodorescu and colleagues turned off the gene AGL. The result was dramatic.
"In tumors that were seeded in mouse models, it was only the cells low in AGL that were able to grow," Theodorescu said.
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Other genes slightly lowered in these successful tumors included INMT, OSR2, ZBTB4 and GPR107, but decrease in AGL far outstripped the others and put AGL at the top of our list for further exploration," he added.
Interestingly, this gene is also mutated in a hereditary liver disease called glycogen storage disease 3 (GSDIII). In GSDIII, loss of AGL makes cells unable to efficiently process glycogen and so excess glycogen builds up in the liver.
With the finding of low AGL in liver cancer and related hints from GSDIII, Theodorescu and colleagues turned to the questions of how AGL drives cancer growth, and whether AGL-driven growth is an artifact of lab conditions or is in fact a feature of the human disease.
The study is published in the Journal of the National Cancer Institute.