Researchers have discovered how a particular protein affects the growth and spread of colon cancer in humans. The study not only improves our understanding of why this type of cancer can be aggressive in some people, but it also highlights a potential treatment target.
Cancer cells produce molecules that can be either up- or downregulated, influencing the growth and spread of the disease. An understanding of these molecules, the pathways that control them, and how they become dysfunctional in cancer states is key to not only better understanding cancer but to developing an effective treatment.
Now, researchers from the Yong Loo Lin School of Medicine at the National University of Singapore (NUS) have made a discovery that could change the treatment of colorectal cancer (CRC), also called colon cancer: the major role that a protein molecule, DUSP6, plays in promoting the growth of the third most common cancer in the world.
“In CRC, higher levels of DUSP6 have been found in tumors, where it helps the cancer cells grow faster, spread more easily, and leads to poorer outcomes for patients,” said Associate Professor Zhang Yongliang from NUS Medicine’s Department of Microbiology and Immunology and the study’s corresponding author. “This unexpected role highlights why DUSP6 is now seen as a possible target for new treatments.”
Now, the relationship between DUSP6 (dual specificity phosphatase 6) and different types of cancers is nothing new, but it’s complicated (more on that later). Its effect on cancer growth will take some explanation.
An important cellular pathway is the mitogen-activated protein kinase (MAPK) pathway, which plays a critical role in integrating external signals to control aspects of cellular behavior, including growth and proliferation, differentiation, survival and death. DUSP6 regulates the MAPK pathway, specifically extracellular signal-regulated kinases 1 and 2 (ERK1/2). Here’s how it works under normal circumstances:
- In response to signals from the MAPK pathway, ERK1/2 is activated by phosphorylation (the addition of a phosphate group).
- Being a phosphatase, DUSP6 dephosphorylates (removes phosphate groups from) ERK1/2, turning off the signaling pathway. This dephosphorylation/deactivation serves as a negative feedback mechanism, preventing overstimulation of the pathway.
- Through dephosphorylation, DUSP6 helps control the duration and intensity of ERK signaling, which is crucial for avoiding excessive or prolonged activation that could result in uncontrolled cell growth or other harmful cellular behaviors.
However, levels of DUSP6 expression and its activity vary depending on specific signaling contexts. Insofar as cancer is concerned, DUSP6’s function appears to vary depending on the cancer type. Studies have shown that in lung and nasopharyngeal cancers and melanoma, DUSP6’s inhibition of ERK1/2 activation acts as a tumor suppressor. Whereas, in other cancer types – gastric, cervical, and ovarian cancers and glioblastomas – DUSP6 expression may increase tumor growth. However, the role of DUSP6 in CRC is unclear, prompting the researchers to undertake the present study.
The researchers generated colon cancer cells that overexpressed DUSP6 and cells in which the DUSP6 gene was knocked out. Cells producing higher levels of DUSP6 showed increased proliferation, and their growth remained significantly higher than control cells. In contrast, the loss of DUSP6 resulted in a significant reduction in cell growth. Overexpressing cells showed reduced activation of ERK1/2, whereas its activation was increased in the knockout cells. In addition, cells migrated 60% faster in DUSP6 overexpressing cells compared to the control, whereas migration was reduced by 60% in the knockout cells. In in vitro tests, measuring the migration of cells from one location to another provides information on cancer invasion and metastasis.
Next, the researchers analyzed DUSP6 expression in primary tumors and adjacent normal tissues from 81 patients with CRC. They found that, overall, DUSP6 protein expression was higher in the tumor tissues than in adjacent tissues. When they grouped patients according to tumor DUSP6 expression level, the researchers found that high DUSP6 expression was associated with overall poorer survival than low DUSP6 expression. Patient survival rate was about 20% lower at around 60 months post-first diagnosis of CRC in those with high DUSP6 levels.
“Our research not only explains why some colon cancers are so aggressive but also gives us a clear target to develop new treatments,” Zhang said, referring to potential therapies that target DUSP6.
The study was published in the journal Nature Communications.