Loss of transcription factor USF1 speeds up H. pylori carcinogenesis

Last Updated: 2020-01-01

By David Douglas

NEW YORK (Reuters Health) - Upstream stimulatory factor 1 (USF1) plays an important role in protection of p53 and its tumor-suppressing response to H. pylori infection, according to researchers.

And as Dr. Eliette Touati told Reuters Health by email, "Our study demonstrates that the loss of transcription factor USF1 accelerates gastric carcinogenesis caused by Helicobacter pylori."

The expression of USF1, which aids stabilization of p53 in response to genotoxic stress, is known to be reduced by H. pylori, Dr. Touati of Institut Pasteur, in Paris, and colleagues note Dr. Touati of Institut Pasteur, in Paris, and colleagues note in Gut.

To investigate the effects of USF1 deregulation, the team studied human gastric epithelial cells, mice infected with H. pylori and data from The Cancer Genome Atlas (TCGA) on gastric-cancer patients.

In mice, loss of USF1 promoted H. pylori-induced carcinogenesis and animals deficient in USF1 showed both p53 depletion and accelerated development and severity of H. pylori-induced gastric lesions.

"More importantly," the researchers point out, "these mice recapitulate the sequential gastric preneoplastic cascade described in human pathology."

The TCGA data showed that low USF1 and p53 levels were associated with low overall survival in human gastric cancer.

For every patient, the teams writes, "the mRNA expression levels of USF1 and p53 are correlated . . . and consequently impact their transcriptional function leading to a significant downregulation of pathways, notably p53-signalling, DNA repair (base excision repair, nucleotide excision repair) and cell cycle regulation in patients with low versus high survival."

H. pylori-mediated USF1 depletion, the researchers observe, "diminishes the stabilization of p53 that is known to contribute to genetic instability and oncogenic properties of the infection."

Thus, say the researchers, "H. pylori-positive gastric tumors with low USF1 and TP53 levels may identify a subgroup of patients with poor prognosis."

"These data," concluded Dr. Touati, "are of clinical relevance, making USF1 a potential biomarker for gastric cancer susceptibility and a new therapeutic target in the treatment of this cancer."

The study was funded in part by the Odyssey Reinsurance Company. The authors declare no conflicts of interest.

SOURCE: https://bit.ly/3697pDT Gut, online December 10, 2019.