SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Gastric cancer (GC) is a leading cause of cancer mortality globally.
• The role of Syndecan-2 (SDC2) in GC pathogenesis and its molecular mechanisms are currently unknown.

Purpose of the Study:

• To investigate the role and molecular mechanisms of SDC2 in gastric cancer.
• To explore SDC2 as a potential diagnostic marker and therapeutic target for GC.

Main Methods:

• Bioinformatic and experimental analyses were employed.
• Investigated SDC2 expression, its correlation with prognosis, and its effects on GC cell growth and invasion.
• Examined the interaction between SDC2, PDK1, and AKT signaling.
• Assessed the role of SDC2 in the FGF2-AKT axis.
• Identified USP14 as a key regulator of SDC2 stability and tested a USP14 inhibitor (IU1).

Main Results:

• SDC2 was highly expressed in GC, correlating with poor patient prognosis.
• SDC2 depletion suppressed GC cell growth and invasion; SDC2 overexpression had opposite effects.
• SDC2 overexpression activated the AKT signaling pathway via interaction with PDK1-PH domain, promoting AKT activation.
• SDC2 acted as a co-receptor for FGF2, contributing to the FGF2-AKT signaling axis in GC.
• USP14 stabilizes SDC2, leading to its upregulation in GC tissues.
• The USP14 inhibitor IU1 reduced SDC2 levels in GC cells.

Conclusions:

• SDC2 functions as a novel oncogene in gastric cancer.
• SDC2 plays a critical role in GC progression through the AKT signaling pathway and FGF2-AKT axis.
• USP14-mediated SDC2 stabilization is a key mechanism for SDC2 upregulation in GC.
• SDC2 represents a promising diagnostic marker and therapeutic target for gastric cancer.