The GDF11 represses the Stat3 signaling pathway, conferring metabolic, inflammatory, and oncogenic restrictions in cells derived from human hepatocellular carcinoma.

Introduction and Objectives

GDF11 has shown potential in displaying anti-tumor effects in cells derived from human HCC, but the molecular mechanisms that lead to this, as well as the early transcriptomic response of GDF11 in HCC, remain a mystery. To identify potential targets for therapeutic intervention revealed by GDF11 treatment in HCC.

Materials and Patients

Huh7 cells were treated for 12 h with 50 ng/ml of GDF11, and sequencing was performed using the Illumina HiSeq4000 platform. The results were filtered with a p≤0.01, ± 1.5-fold change, and an FDR= 0.05. Functional and enrichment analysis was done using the Ingenuity Pathway Analysis (IPA) program.

Results

Our data show 1450 differentially expressed genes. It is observed that GDF11 has a profound impact on highly oncogenic pathways, highlighting the Stat3 pathway, beta-catenin, and HIF-1 alpha, among others. Functional analysis revealed that GDF11 could reduce cholesterol and lipid metabolism in general, inflammation, drug resistance, and stemness capacity. It is noteworthy that tumors grown under a lipid-rich environment exhibit significant activation of Stat3, so the decrease in the molecular signature of Stat3 induced by GDF11 strongly suggests a mechanism mediated by the repression of the pathway of this factor transcription, impacting metabolism, inflammation, differentiation, and drug resistance.

Conclusions

Our study's novel finding is that GDF11 represses the Stat3 signaling pathway, thereby imposing metabolic, inflammatory, and oncogenic restrictions. GDF11 represents a good promise in the treatment of HCC.

Ethical statement: The present work has not involved animals or patients.

Declaration of interests: None.

Funding: UAM-2024, and Conahcyt.