Colon cancer is one of the leading causes of cancer-related deaths worldwide, and researchers are hard at work to understand the disease’s complex molecular underpinnings. Now, a study from researchers at the University of Pennsylvania has identified two related genes in the Musashi family that are required for colon cancer to develop. The team state that their findings challenge a paradigm in the field whereby activation of a molecular signaling cascade known as the Wnt pathway is held responsible for the majority of colon cancer cases in humans. The opensource study is published in the journal Cell Reports.
Previous studies show that MSI1 is expressed in colon cancer, the mechanism by which it acts and its functional requirement for the disease is not well understood. Earlier studies from the lab found that the related protein MSI2 could trigger activation of cellular metabolic processes that fuel cancerous cells in the intestines. Considering the expression patterns of these two proteins during homeostasis the group hypothesized that their function when they were hijacked by cancer could be similar in supporting tumour growth. Therefore, they took both proteins into account. The current study shows that the Musashi genes, MSI1 and MSI2, act in a path parallel to the Wnt pathway and may be equally important for driving colon cancer; the work also indicates that the two genes, which encode RNA-binding proteins, are functionally redundant.
The current study shows that when overexpression of MSI1 was induced in the intestine of mice, the cells of the intestine began to divide rapidly and lost their ability to differentiate, just as mice with inducible overexpression of MSI2 had. Results show that inducing MSI1 turned on a similar set of genes as MSI2 overexpression did, including genes related to RNA processing and translation, necessary processes for manufacturing the required components for cancer’s rapid cell growth. The analysis also revealed that activating MSI1 caused a set of genes to be expressed that match the effect of losing the function of APC, a tumour suppressor gene that is inactivated in more than 80% of cases of human colon cancer. Data findings show that these proteins are functioning in the same pathways and acting redundantly because they are binding similar proteins and when overexpressed the phenotype is identical.
To confirm whether both MSI1 and MSI2 are necessary for tumour formation, the lab inhibited one or the other or both in several human colorectal cancer cell lines. Results show that inhibiting only MSI1 blocked growth of some cell lines, whereas inhibiting both MSI1 and MSI2 together effectively blocked cell growth in all of them. Data findings show that adding an inhibitor of Beta-catenin, the downstream mediator of the Wnt pathway, synergized with MSI inhibition to completely block tumour cell growth.
To validate these findings the group developed mice with a heightened risk of developing colorectal tumours, which could be induced to either lack MSI1, MSI2 or both in their intestinal tissue. The team observed that while knocking out one or the other MSI proteins didn’t affect tumour formation, knocking out both genes markedly reduced the tumours in these mice. Performing the same experiments in mice that develop an inflammation-induced form of colorectal cancer that more closely resembles the human disease, the group also observed that Msi loss was completely protective against tumour formation.
The team surmise that by deleting both MSIs it has been shown that tumours are completely blocked from forming, leaving the tissue perfectly normal. They go on to add that this is interesting because it’s what a study would look for in an ideal cancer target, something that, when you inhibit it, can block cancer progression without adversely effecting the normal tissue. For the future, the researchers state they now plan to investigate which specific cell types the MSI proteins act upon and to delve deeper to understand how APC inactivation triggers colon cancer through Beta-catenin and other avenues.
Source: University of Pennsylvania