Esophageal cancer activates the ancient virus hidden in the human genome and also provides new targets for cancer treatment

According to the latest global cancer burden data released by the International Agency for Research on Cancer of the World Health Organization in 2020, esophageal cancer is the eighth number of new malignant tumors in the world and the sixth number of deaths per year.

Esophageal cancer is particularly prominent in China. Half of the new and dead esophageal cancers in the world each year are in China.

Adam Bass’s team from the Harvard Medical School Research Institute published “Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence” in《Nature Genetics 》.

The study found that the oncogene SOX2 in esophageal cancer activates the expression of ancient retroviruses embedded in the human genome, thereby prompting esophageal cancer cells to become dependent on ADAR1.

The research team used esophageal organoids created in mouse tissues and found that a specific oncogene SOX2 in esophageal cancer can induce the expression of many ERVs. The accumulation of double-stranded RNA caused by the expression of ERV may have a toxic effect on cells.

The research team further discovered that the ADAR1 enzyme (a double-strand specific RNA editing enzyme) can quickly degrade these double-stranded RNAs. Cancer immunotherapy, represented by PD-1/PD-L1 inhibitors, is already being used in some patients with esophageal cancer and can extend their survival by several months.

The research team established an esophageal organoid to simulate and track the development of cancer from a normal esophagus to a complete transformation. The organoids in this study start from the overexpression of the SOX2 gene, and SOX2 gene amplification is one of the gene characteristics of esophageal cancer.

The team analyzed differences in SOX2 activity in normal and cancerous tissues using esophageal organs. In organs with both SOX2 overexpression and deletion of the tumor suppressor gene p53/p16, we found that SOX2 turns on the expression of various oncogenes and activates endogenous retroviruses (ERVs), making cancer cells more dependent on ADAR1.

In view of the above findings, blocking ADAR1 is likely to have a direct effect on esophageal cancer, and it may also play a greater value by improving the effectiveness of cancer immunotherapy on patients with esophageal cancer.


[1]Zhong Wu. et al.Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nature Genetics. 2021DOI:articles/s41588-021-00859-2