Integrated Multi-Omics and Spatial Transcriptomics Identify FBLL1 as a Malignant Transformation Driver in...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Hepatocellular carcinoma (HCC) exhibits significant intratumoral heterogeneity and leads to poor patient outcomes.
• Dysregulated ribosome biogenesis is a known hallmark of cancer, but its specific role in HCC pathogenesis is unclear.
• Identifying novel molecular drivers is crucial for understanding and treating HCC.

Purpose of the Study:

• To identify and characterize novel prognostic candidate genes in hepatocellular carcinoma.
• To elucidate the molecular mechanisms by which these genes contribute to HCC progression.
• To evaluate potential therapeutic targets for liver cancer.

Main Methods:

• Integration of multi-omics data from TCGA and ICGC cohorts to identify candidate genes.
• Analysis of gene distribution using single-cell RNA sequencing and spatial transcriptomics.
• In vitro and in vivo functional validation through gene knockdown and overexpression experiments.
• Elucidation of molecular mechanisms via transcriptomic analysis and Western blotting.

Main Results:

• FBLL1 was identified as a key prognostic gene, significantly upregulated in HCC and associated with poor survival.
• FBLL1 expression was enriched in malignant hepatocytes within tumors.
• FBLL1 knockdown inhibited HCC cell proliferation, while its overexpression promoted tumorigenesis in vivo.
• FBLL1 overexpression correlated with increased c-Myc and EGFR ligands, impacting the EGFR-MAPK pathway.

Conclusions:

• FBLL1 is a novel regulator implicated in the malignant transition of HCC.
• FBLL1 promotes HCC by facilitating ligand-dependent EGFR-MAPK pathway activation alongside c-Myc upregulation.
• FBLL1 represents a potential therapeutic target for disrupting oncogenic signaling in liver cancer.