TLE3-AKR1B1 signaling axis participating in the malignant progression of gastrointestinal stromal tumor by regulating galactose metabolism

KIT and / or PDGFRA activation mutation is the initial molecular event of gastrointestinal stromal tumor (GIST), and the molecular mechanism leading to the malignant progression of GIST needs to be further studied and broken through. This study aims to understand the mechanism of malignant progression of GIST from the perspective of metabolic reprogramming and provide a new target for the treatment of GIST.

In the present study, transcriptome and metabolome were used to test GIST tumor tissue and adjacent normal tissue samples with different degrees of malignancy. Galactose metabolism and its rate-limiting enzyme AKR1B1 were involved in the malignant progression of GIST through the combined analysis of transcriptome, targeted proteome and metabolome. Expression of AKR1B1, and its correlation with patients’ prognosis were analyzed using immumohistochemical staining, followed with the determination of function and underlying mechanism.

AKR1B1 was upregulated in GIST by regulating galactose metabolism. The transcription factor TLE3 inhibits GIST cell proliferation and mitosis by targeting AKR1B1. Analysis of the correlation between TLE3 and AKR1B1 expression shows that AKR1B1 and TLE3 are abnormally expressed in GIST, and TLE3 can negatively regulate the expression of AKR1B1, which is closely related to the prognosis of patients. Epalrestat, a small molecule inhibitor of AKR1B1, can regulate the expression of metabolites lactose, inositol, sucrose, UDP-d-galactose and D-mannitol in the galactose metabolic pathway, leading to the redirection of metabolic flux between branches of galactose metabolic pathway to cope with the inhibition of AKR1B1 and maintain the dynamic balance of galactose metabolism.

This study shows that TLE3-AKR1B1 signaling axis can participate in GIST malignant progression through regulation of galactose metabolism, providing experimental data for understanding the mechanism of GIST malignant progression from the perspective of metabolic reprogramming, and also providing a new target for GIST treatment.

The authors.

Has not received any funding.

All authors have declared no conflicts of interest.