Selenium signal found in colorectal cancer: studyJun. 29, 2023, 9:17 AM
by Bill Snyder
An antioxidant transporter of the trace mineral selenium that protects against inflammatory bowel disease has the opposite effect in colorectal cancer, where it promotes tumor growth, researchers at Vanderbilt University Medical Center have reported.
The study by Jennifer Pilat, PhD, Christopher Williams, MD, PhD, and colleagues, is among the first to link the selenium transporter, selenoprotein P or SELENOP, to activation of a tumor-promoting signaling pathway in the colon.
Their findings, reported in the Journal of Clinical Investigation, add to the complexity of the genetic, environmental and lifestyle factors that contribute to colorectal cancer, the nation’s third leading cancer killer.
“We discovered a never-before-described role for SELENOP in a signaling pathway that’s incredibly important in both normal intestinal biology and colorectal cancer,” said Pilat, the paper’s first author and a former graduate student in Williams’ lab who recently defended her doctoral thesis.
“Jennifer’s persistence paid off on a very tough project,” said Williams, professor of Medicine, associate dean of Physician-Scientist Education and Training in the Vanderbilt University School of Medicine, and the paper’s senior author.
“As a result, we now have a better understanding of the complexities underlying the pathogenesis of colorectal cancer,” he said. “Additionally, we uncovered a new role for a key selenoprotein in modulating intracellular signaling networks.”
Williams and his colleagues have made important contributions to understanding the role of SELENOP and related proteins in health and disease.
SELENOP uploads its selenium cargo from the bloodstream to various tissues by binding to lipoprotein receptor-related proteins (LRPs) on cell surfaces. Some LRPs, by activating the WNT signaling pathway, promote the development of tumors.
In collaboration with Ken Lau, PhD, professor of Cell & Developmental Biology, and using a technique called single-cell RNA-sequencing, or scRNA-seq, to measure the expression of specific genes, the researchers determined that expression of the Selenop gene progressively increased from colorectal stem cells to pre-cancerous adenoma and carcinoma cells.
Deleting or “knocking out” Selenop in a mouse model reduced the incidence and size of colon tumors.
Three-dimensional cultures of epithelial cells called organoids isolated from the tumors of these mice had reduced expression of WNT target genes. Restoring SELENOP reversed WNT suppression.
Finally, the researchers determined that SELENOP activates the WNT signaling pathway by binding to WNT co-receptors LRP5 and LRP6.
“Our findings add yet another layer of complexity to the multimodal mechanisms of WNT signaling regulation in the intestine,” the researchers concluded.
“This justifies further research into SELENOP’s contributions to sporadic colorectal carcinogenesis.”
In addition to Lau, co-authors from VUMC were Rachel Brown, PhD, Zhengyi Chen, Nathaniel Berle, Adrian Othon, M. Kay Washington, MD, PhD, Shruti Anant, Victoria Ng, PhD, Joshua Thompson, MD, PhD, Justin Jacobse, MD, MSc, Jeremy Goettel, PhD, Ethan Lee, MD, PhD, Yash Choksi, MD, and Sarah Short, PhD.