Hypoxia-Induced TGFBI Promotes Bladder Cancer Progression by Creating a Stemness Regulation Loop through Stabilizing...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Cancer stem cell (CSC) stemness is vital for tumor progression, but its regulation is not fully understood.
• Transforming growth factor beta induced protein (TGFBI) is upregulated under hypoxia in bladder cancer (BLCA).

Purpose of the Study:

• To investigate the role of hypoxia-induced TGFBI in maintaining CSC stemness and promoting BLCA progression.
• To elucidate the molecular mechanisms by which TGFBI influences the tumor microenvironment and CSCs.
• To explore the therapeutic potential of targeting the TGFBI/GDF15 axis in BLCA.

Main Methods:

• Analysis of hypoxic TGFBI expression in BLCA patient samples.
• Investigating the interaction between TGFBI and growth differentiation factor 15 (GDF15) using biochemical assays.
• Studying the effect of TGFBI knockdown and GDF15 inhibition on CSC stemness, proliferation, and chemotherapy response in BLCA models.
• Examining the TGFBI/GDF15 feedback loop involving cancer-associated fibroblasts and TGFβ signaling.

Main Results:

• Upregulated hypoxic TGFBI in BLCA correlates with advanced disease and poor prognosis.
• TGFBI stabilizes GDF15, leading to its aberrant function and secretion.
• Secreted GDF15 enhances CSC-related gene expression and activates cancer-associated fibroblasts via a TGFβ-TGFBI self-regulatory loop.
• TGFBI knockdown or GDF15 inhibition reduces stemness proteins, suppresses CSC self-renewal, and improves chemotherapy efficacy.

Conclusions:

• TGFBI plays a critical role in maintaining BLCA stemness and driving tumor progression.
• The TGFBI/GDF15 axis represents a novel mechanism for CSC regulation in the tumor microenvironment.
• Targeting the TGFBI/GDF15 axis offers a promising therapeutic strategy to overcome chemotherapy resistance in BLCA.