Gene Suppressing Some Cancer Types Could Be Lethal in Colorectal Cancer

January 5, 2016
Greg Kennelty

A gene associated with the suppression of tumor growth has been found to act in the opposite manner in some forms of colorectal cancer (CRC), according to researchers at the University of Missouri School of Medicine.

Sharad Khare, PhD

A gene associated with the suppression of tumor growth has been found to act in the opposite manner in some forms of colorectal cancer (CRC), according to researchers at the University of Missouri School of Medicine.

“The gene known as Sprouty2 has previously been shown to protect against metastasis, or the spreading of cancer to other parts of the body, in breast, prostate and liver cancer,” said Sharad Khare, PhD, associate professor of research, Missouri University School of Medicine’s Division of Gastroenterology and Hepatology, and lead author of the study, in a press release.1“However, our recent molecular studies found that this gene may actually help promote metastasis instead of suppress it.”

According to the study,2published inOncogene, Sprouty (SPRY) is a family of four types of intracellular regulators. SPRY-regulated receptor tyrosine kinase signaling is associated with growth, differentiation, and tumorigenesis. Of the 4 SPRY types, SPRY2 appears across numerous cancer types. Expression of SPRY2 is reduced in breast, prostate, lung, and liver cancers, while expression is increased in CRC.

The researchers formed a hypothesis that SPRY2 and miR-194—dependent suppression of AKT2, among other repressors, of E-cadherin could account for upregulation of E-cadherin and inhibition of cancer cell migration and invasion.

The team then tested this with recombination of floxed SPRY1 and SPRY2 alleles in mouse embryonic fibroblasts and showed increased expression of epithelial markers and lowered cell migration. Analysis of the expression profile in CRC also showed increased SPRY1 and SPRY2 transcripts and an inverse expression pattern between AKT2 and E-cadherin. Together, this study indicates that SPRY is a target of therapeutic intervention in CRC metastasis.

"The expression of SPRY in human CRC is a contentious issue and has not been explored extensively. We have demonstrated upregulation of SPRY2 protein in a small number of matched control CRC samples. Our results were supported by a study which showed upregulation of SPRY2 in undifferentiated high-grade tumors and at the invasive front of low-grade carcinomas," said Zhang et al in the study.

The study states that the correlation between SPRY2 and the re-regulation of transcription factors and/or methylation of the miR-194 promoter is not clear from the results of the study, and that further investigation is needed. Despite the opacity in some dimensions of the results, Khare states that the finding is a massive step toward prolonging the life expectancy of patients with CRC.

“This finding is a very significant step in our understanding of metastasis in colorectal cancer, but it’s important to note that we believe this phenomenon may occur in only a subset of colorectal cancer patients,” Khare said. “We don’t yet know why this is the case, but we hope to determine if there is a correlation between the upregulation of this gene and the life expectancy of patients with colorectal cancer. Future studies will help us understand who may be at risk, and ultimately, if personalized treatments can be planned to target this gene.”

According to Cancer.gov,3CRC is the third-most commonly occurring non-skin cancer and the second leading cause of cancer-related deaths in the United States. These deaths are most commonly attributed to recurrence and metasteses.1Occurrence rates of CRC are higher in men, though both sexes show similar incidence rates through age 39.

References

  1. University of Missouri Health. Gene thought to suppress cancer may actually promote spread of colorectal cancer. 2016. http://medicine.missouri.edu/news/tumor-gene.php. Accessed January 4, 2016.
  2. Zhang Q, Wei T, Shim K, et al. Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial—mesenchymal transition.Oncogene. 2015. doi:10.1038/onc.2015.365.
  3. National Cancer Institute. A snapshot of colorectal cancer. 2016. http://www.cancer.gov/research/progress/snapshots/colorectal. Accessed January 4, 2016.