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PFKFB3 Increases IL-1 β and TNF- α in Intestinal Epithelial Cells to Promote Tumorigenesis in Colitis-Associated Colorectal Cancer

Colorectal cancer (CRC) is significantly correlated with inflammatory bowel disease, which usually manifests as chronic relapsing-remitting colitis. Phosphofructo-2-kinase/fructose-2,6-biophosphatase 3 (PFKFB3) can catalyze to produce fructose-2,6-bisphosphate and function as an oncogene. In this study, we revealed the function of PFKFB3 in colitis-associated CRC (CAC) and the potential mechanism. RT-qPCR and Western blot were utilized to detect the level of PFKFB3 expression. Increased PFKFB3 expression was observed in the mouse CAC model and CAC patient samples. We identified that overexpression of PFKFB3 in intestinal epithelial cells (IECs) could increase the proliferation, migration, and invasion of CRC cells by the coculture system. Mechanistically, overexpression of PFKFB3 induced phospho-p65 and promoted the expression of IL-1β and tumor necrosis factor alpha (TNF-α) in the development of colitis and CAC. In addition, PFK158, the PFKFB3 inhibitor, could reduce the CRC cell viability, migration, and invasion caused by PFKFB3 overexpression. In conclusion, overexpression of PFKFB3 promoted tumorigenesis in CAC by inducing phospho-p65 and expression of IL-1β and TNF-α. Our study suggested that PFKFB3 acted as a potential treatment target for CAC.

 

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The study you provided explores the role of Phosphofructo-2-kinase/fructose-2,6-biophosphatase 3 (PFKFB3) in colitis-associated colorectal cancer (CAC) and its potential mechanisms. Here's a breakdown of the findings and their significance:

### Background:
- **Colorectal Cancer (CRC) and Inflammatory Bowel Disease (IBD):** Colorectal cancer is closely linked to inflammatory bowel diseases, particularly chronic relapsing-remitting colitis.
- **PFKFB3:** PFKFB3 is an enzyme that plays a role in producing fructose-2,6-bisphosphate and acts as an oncogene, contributing to cancer development.

### Study Findings:

1. **Increased PFKFB3 Expression:**
   - The study observed elevated levels of PFKFB3 expression in both a mouse model of CAC and samples from CAC patients.

2. **Effect on CRC Cells:**
   - Overexpression of PFKFB3 in intestinal epithelial cells (IECs) was found to enhance the proliferation, migration, and invasion of CRC cells. This suggests that elevated PFKFB3 levels contribute to the aggressiveness of CRC.

3. **Mechanistic Insights:**
   - Overexpression of PFKFB3 led to the activation of phospho-p65 and increased the expression of pro-inflammatory cytokines IL-1β and tumor necrosis factor alpha (TNF-α). This implies that PFKFB3 might promote inflammation, a known factor in cancer development, through these molecular pathways.

4. **Therapeutic Potential of PFKFB3 Inhibition:**
   - The study utilized PFK158, a PFKFB3 inhibitor, which was able to counteract the effects of PFKFB3 overexpression. PFK158 reduced CRC cell viability, migration, and invasion. This highlights the therapeutic potential of targeting PFKFB3 in CAC treatment.

### Significance and Conclusion:

- **Tumorigenesis Promotion:** The study establishes that overexpression of PFKFB3 promotes tumorigenesis in CAC through the activation of inflammatory pathways involving phospho-p65, IL-1β, and TNF-α.

- **Therapeutic Implications:** Identifying PFKFB3 as a key player in CAC suggests that targeting this enzyme could be a viable treatment strategy. The use of PFK158, an inhibitor, demonstrated its effectiveness in inhibiting the aggressive behavior of CRC cells influenced by PFKFB3.

- **Clinical Relevance:** These findings imply that therapies aimed at inhibiting PFKFB3 might mitigate the progression of CAC, providing a potential avenue for future clinical research and treatment development.

In summary, this study sheds light on the molecular mechanisms underlying the relationship between PFKFB3, inflammation, and CAC. It suggests that PFKFB3 inhibition could be a promising therapeutic approach for managing colitis-associated colorectal cancer.

Related Products

Cat.No. Product Name Information
S8807 PFK158 PFK158 is a potent and selective inhibitor of PFKFB3. It has improved PK properties and causes ~80% growth inhibition in several mouse models of human-derived tumors.

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