Intestinal epithelial cell-specific CD98 expression regulates tumorigenesis in Apc(Min/+) mice

Area of Science:

• Molecular Biology
• Oncology
• Gastroenterology

Background:

• Transmembrane glycoprotein CD98 (CD98) is upregulated in carcinomas, including colorectal cancer.
• CD98 regulates integrin signaling, impacting cell proliferation and survival.
• Previous studies explored CD98's role in intestinal homeostasis and inflammation-associated tumorigenesis.

Purpose of the Study:

• To investigate the contribution of CD98 to intestinal tumorigenesis in Apc(Min/+) mice.
• To elucidate the underlying mechanisms by which CD98 influences tumor development.
• To assess the therapeutic potential of modulating CD98 expression in intestinal cancer.

Main Methods:

• Generated and analyzed transgenic mice with intestinal epithelial cell (IEC)-specific CD98 overexpression (Tg) crossed with Apc(Min/+) mice.
• Assessed intestinal adenoma formation, incidence, and size in genetically modified mice.
• Validated findings using mice with IEC-specific CD98 downregulation (CD98(flox/+)VillinCre).

Main Results:

• IEC-specific CD98 overexpression in Apc(Min/+) mice significantly increased tumor incidence and size.
• Overexpression led to enhanced IEC proliferation, decreased apoptosis, and increased oncogenic proteins c-myc and cyclin-D1.
• CD98 overexpression boosted proinflammatory cytokine and chemokine production, while downregulation attenuated these effects and reduced tumor growth.

Conclusions:

• CD98 exerts an oncogenic activity in intestinal tumorigenesis.
• CD98 regulates tumor growth and survival by modulating IEC proliferation, apoptosis, and inflammatory responses.
• Targeting CD98 in intestinal epithelial cells offers a potential strategy for colorectal cancer intervention.