3-Formylchromone Counteracts STAT3 Signaling Pathway by Elevating SHP-2 Expression in Hepatocellular Carcinoma

Simple Summary STAT3 acts as a potential tumor-promoting transcription factor that gets aberrantly activated in several types of human cancers and plays a crucial role in tumor progression and metastasis. STAT3 expression has been correlated with a dismal prognosis and poor survival. In this study, we have demonstrated that 3-formylchromone inhibits the STAT3 signaling in HCC cells by modulating SHP-2 expression. It also effectively diminished the tumor growth and subsequent reduction in metastasis in the HCC mouse model without exhibiting any major side effects. Hepatocellular carcinoma (HCC) is one of the leading cancers that contribute to a large number of deaths throughout the globe. The signal transducer and activator of transcription 3 (STAT3) is a tumorigenic protein that is overactivated in several human malignancies including HCC. In the present report, the effect of 3-formylchromone (3FC) on the STAT3 signaling pathway in the HCC model was investigated. 3FC downregulated the constitutive phosphorylation of STAT3 and non-receptor tyrosine kinases such as JAK1 and JAK2. It also suppressed the transportation of STAT3 to the nucleus and reduced its DNA-binding ability. Pervanadate treatment overrode the 3FC-triggered STAT3 inhibition, and the profiling of cellular phosphatase expression revealed an increase in SHP-2 levels upon 3FC treatment. The siRNA-driven deletion of SHP-2 led to reinstate STAT3 activation. 3FC downmodulated the levels of various oncogenic proteins and decreased CXCL12-driven cell migration and invasion. Interestingly, 3FC did not exhibit any substantial toxicity, whereas it significantly regressed tumor growth in an orthotopic HCC mouse model and abrogated lung metastasis. Overall, 3FC can function as a potent agent that can display antitumor activity by targeting STAT3 signaling in HCC models.

Automated summary

This study demonstrates that 3-formylchromone inhibits the activated STAT3 signaling in hepatocellular carcinoma cells and effectively reduces tumor growth and metastasis in a mouse model. The researchers also found that 3-formylchromone does not cause substantial toxicity. Therefore, it has the potential to be a powerful agent for targeting STAT3 signaling in hepatocellular carcinoma.