Fibulin-3 promotes muscle-invasive bladder cancer.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Urothelial carcinoma, the most common bladder cancer, is classified as non-muscle-invasive (Ta-T1) or muscle-invasive (≥T2).
• Non-muscle-invasive bladder cancers frequently recur and can progress to muscle-invasive disease.

Purpose of the Study:

• To identify genes differentially expressed between T1 and T2 bladder cancer stages.
• To pinpoint key regulators of bladder cancer progression and invasion.

Main Methods:

• RNA sequencing (RNA-Seq) on T1 and T2 bladder cancer tissues.
• Analysis of public bladder cancer profiling data for gene prioritization.
• Quantitative reverse transcriptase-PCR (qRT-PCR) for validation.
• In vitro cell line experiments and in vivo murine orthotopic bladder cancer models.

Main Results:

• Fibulin-3 (FBLN3, also known as EFEMP1) was identified as highly expressed in T2 vs T1 bladder cancer and in aggressive vs indolent disease.
• FBLN3 expression correlated with bladder cancer cell line invasiveness, and its modulation directly impacted invasion.
• FBLN3 knockdown reduced muscle-invasive bladder cancer (MIBC) incidence in a murine model and decreased insulin-like growth factor-binding protein-5 (IGFBP5) expression.
• Restoring IGFBP5 rescued the invasive and migratory potential of FBLN3-knockdown cells.

Conclusions:

• Fibulin-3 acts as a pro-invasive factor in bladder cancer, potentially mediating its effects through IGFBP5.
• FBLN3 and IGFBP5 show potential as biomarkers for aggressive bladder cancer and as therapeutic targets.