TLX3 repressed SNAI1-induced epithelial-mesenchymal transition by directly constraining STAT3 phosphorylation and...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• TLX3 is a transcription factor crucial for nervous system development.
• While known for its role in leukemia, TLX3's function in hepatocellular carcinoma (HCC) is unexplored.
• Aberrant TLX3 expression is implicated in various cancers.

Purpose of the Study:

• To investigate the expression and function of TLX3 in hepatocellular carcinoma (HCC).
• To determine the correlation between TLX3 expression and clinicopathological features, patient survival, and therapeutic response in HCC.
• To elucidate the underlying molecular mechanisms of TLX3's role in HCC progression and epithelial-mesenchymal transition (EMT).

Main Methods:

• Analysis of TLX3 expression in HCC patient samples.
• ITRAQ proteomic profiling and gene expression microarray analysis.
• In vitro cell viability, proliferation, migration, and invasion assays.
• In vivo xenograft studies.
• Western blot analysis to assess protein phosphorylation and expression.

Main Results:

• TLX3 expression was decreased in 68% of HCC cases and associated with poor survival.
• TLX3 downregulation correlated with increased p-STAT3, SNAI1, Vimentin, and decreased E-cadherin.
• TLX3 overexpression inhibited HCC cell growth, migration, invasion, and enhanced 5-FU sensitivity, while attenuating EMT.
• TLX3 suppressed IL-6/STAT3 signaling by inhibiting STAT3 phosphorylation and SNAI1 expression.

Conclusions:

• Loss of TLX3 expression promotes HCC progression and metastasis by activating the IL-6/STAT3/SNAI1 signaling pathway, leading to EMT.
• TLX3 downregulation contributes to poor patient prognosis and reduced sensitivity to 5-FU chemotherapy.
• TLX3 acts as a tumor suppressor in HCC, and its restoration holds therapeutic potential.