Early Developmental Gene May Play a Role in Endometriosis

Twist may increase the migration and invasion of connective tissue cells in the lining of the uterus.

Key Points

Highlights:

• An early developmental gene called twist may play a role in the development and spread of endometriosis by mediating epithelial to mesenchymal transition (EMT), a biological process known to promote cell migration and invasion. 

Importance:

• Identifying factors that may play a role in the development of endometriosis can help find new ways of halting the disease.

What's done here:

Researchers collected tissue samples from women with and without endometriosis:

• They analyzed the levels of twist mRNA and protein as well as levels of N‐cadherin, and E‐cadherin, cell adhesion molecules that are markers of EMT.
• The researchers over-expressed twist in the tissue samples they collected to see what would happen to the expression of N‐cadherin, and E‐cadherin following this.
• Finally, researchers explored the migration and invasion of cells in their tissue sample in which they over-expressed twist.

Key results:

• Levels of protein and mRNA of twist and N-cadherin were highest in tissue resembling the lining of the uterus found outside the uterus in ovarian endometriosis and lowest in the normal lining of the uterus of women without endometriosis. (N-cadherin is a marker of mesenchymal or migratory cells).
• The expression of E-cadherin was highest in the normal lining of the uterus in women without endometriosis. 
• The overexpression of twist significantly up-regulated the mRNA and protein expression of N-cadherin and down-regulated that of E-cadherin. (A switch from E-cadherin to N-cadherin expression indicates EMT).
• The overexpression of twist significantly promoted cell migration and invasion.

Limitations:

• These are early experiments that were conducted in tissue samples grown in the laboratory.
• The findings cannot yet support the development of any therapies for endometriosis at this stage but rather add to the basic knowledge about the pathology of the disease.
• More research is needed to decipher the potential therapeutic effect of targeting twist on endometriosis. 

Lay Summary

An early developmental gene called twist may encourage the connective tissue cells of the lining of the uterus to change from being epithelial to being mesenchymal, so-called epithelial to mesenchymal transition (EMT). 

Mesenchymal cells play important roles in biological processes such as tissue repair, scarring, and tumor invasiveness. They are able to migrate, invade other tissues, and are resistant to programmed cell death. EMT is known to contribute to the development and spread of endometriosis.

Identifying new genetic factors contributing to EMT can help scientists develop new ways of targeting these factors and halting the spread of endometriosis.

“Given its critical role in the pathogenesis of endometriosis, twist may be a promising therapeutic target for endometriosis treatment,” the researchers wrote. “Drugs repressing the expression or inhibiting the function of twist may suppress the progress and recurrence of endometriosis.” 

In order to investigate the potential role of twist in cell migration and invasion, the team from China collected tissue samples from women with, as well as without endometriosis. They measured the levels and looked at the distribution of proteins such as Twist, N‐cadherin, and E‐cadherin. They also analyzed the mRNA levels of genes encoding these proteins. mRNA is an intermediate molecule between a gene and its protein product. It is a temporary copy of a gene that is used by the protein-making machinery of the cells. High levels of mRNA indicate that the gene is “highly expressed” or in other words being actively read and copied into mRNA.

Cadherins are a type of cell adhesion molecule that is important for cells to bind to each other. A switch from E-cadherin to N-cadherin expression indicates EMT.

The researchers found that the levels of both the mRNA and protein of twist and N‐cadherin were high in tissue samples collected from women with ovarian endometriosis. These levels were low in samples obtained from the lining of the uterus of women without the disease. Inversely, the levels of E‐cadherin were highest in normal endometrium obtained from women without endometriosis.

The researchers then transfected the tissues that they grew in the laboratory with twist DNA. When they looked at levels of N‐cadherin, and E‐cadherin following transfection, they saw that the levels of N‐cadherin mRNA and protein increased, while levels of E‐cadherin decreased. 

Finally, the researchers looked at the migration and invasion of the connective tissue cells in their sample and saw that the overexpression of twist significantly promoted cell migration and invasion in the tissue samples.

They concluded that twist may play a role in the migration and invasion of connective tissue cells in the lining of the uterus through EMT.

The twist gene provides the instructions to make a type of protein called a transcription factor. Transcription factors bind to the DNA and control the expression of other genes. The protein encoded by the twist gene is known to be essential in early development for the formation of cells that give rise to bones and muscles. 

Previous research has shown that twist plays a role in different cancer types including breast cancer, colon cancer, and hepatocellular carcinoma by promoting cell migration and invasion. 

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/31250947