Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue, and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and one major signal for the induction of EMT is TGFβ, which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We have constructed an EMT network of 70 nodes and 135 edges by integrating the signaling pathways involved in developmental EMT and known dysregulations in invasive HCC. We then used discrete dynamic modeling to understand the dynamics of the EMT network driven by TGFβ. Our network model recapitulates known dysregulations during the induction of EMT and predicts the activation of the Wnt and Sonic hedgehog (SHH) signaling pathways during this process. We show, across multiple murine (P2E and P2M) and human HCC cell lines (Huh7, PLC/PRF/5, HLE, and HLF), that the TGFβ signaling axis is a conserved driver of mesenchymal phenotype HCC and confirm that Wnt and SHH signaling are induced in these cell lines. Furthermore, we identify by network analysis eight regulatory feedback motifs that stabilize the EMT process and show that these motifs involve cross-talk among multiple major pathways. Our model will be useful in identifying potential therapeutic targets for the suppression of EMT, invasion, and metastasis in HCC. Cancer Res; 74(21); 1–15. ©2014 AACR.
Network modeling of TGF{beta} signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals ȷoint Sonic hedgehog and Wnt pathway activation
Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue, and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and one major signal for the induction of EMT is transforming growth factor beta (TGFβ), which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We have constructed an EMT network of 70 nodes and 135 edges by integrating the signaling pathways involved in developmental EMT and known dysregulations in invasive HCC. We then used discrete dynamic modeling to understand the dynamics of the EMT network driven by TGFβ. Our network model recapitulates known dysregulations during the induction of EMT and predicts the activation of the Wnt and Sonic hedgehog (SHH) signaling pathways during this process. We show, across multiple murine (P2E and P2M) and human HCC cell lines (Huh7, PLC/PRF/5, HLE, and HLF), that the TGFβ signaling axis is a conserved driver of mesenchymal phenotype HCC and confirm that Wnt and SHH signaling are induced in these cell lines. Furthermore, we identify by network analysis eight regulatory feedback motifs that stabilize the EMT process and show that these motifs involve cross-talk among multiple major pathways. Our model will be useful in identifying potential therapeutic targets for the suppression of EMT, invasion and metastasis in HCC.
We Need Your Help: Join the Crew of the Ride to Conquer Cancer!
On October 11 and 12, 2014, hundreds of cyclists of all abilities will participate in The Ride to Conquer Cancer® benefiting Penn Medicine’s Abramson Cancer Center. The Ride needs wonderful people like you to help with the following:
- Providing snacks and meals on the route
- Camp set-up
- Providing medical care if you need it
- Marking the route with directional signage
- Driving our event vehicles
- Route safety
- And much more!
Crew Members are the backbone of the event.
They are our bike mechanics, route guides and food distributors. Because of all their hard work and dedication, crew members experience the same perks as the riders, including access to a hot shower, catered meals and a cozy tent at Camp.
Join us today and be part of a great team! Simply visit the Ride to Conquer Cancer website and choose “Individual” to register. Then, you will be guided through the “Crew” registration.
Thank you for supporting The Abramson Cancer Center and The Ride to Conquer Cancer!
Focus on Cancer RSS Feed 2014-09-04 10:00:00
On October 11 and 12, 2014, hundreds of cyclists of all abilities will participate in The Ride to Conquer Cancer® benefiting Penn Medicine’s Abramson Cancer Center. The Ride needs wonderful people like you to help with the following:
- Providing snacks and meals on the route
- Camp set-up
- Providing medical care if you need it
- Marking the route with directional signage
- Driving our event vehicles
- Route safety
- And much more!
Crew Members are the backbone of the event.
They are our bike mechanics, route guides and food distributors. Because of all their hard work and dedication, crew members experience the same perks as the riders, including access to a hot shower, catered meals and a cozy tent at Camp.
Join us today and be part of a great team! Simply visit the Ride to Conquer Cancer website and choose “Individual” to register. Then, you will be guided through the “Crew” registration.
Thank you for supporting The Abramson Cancer Center and The Ride to Conquer Cancer!
Cirp and Inflammatory Bowel Disease
Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and is reported to be associated with refractory inflammatory bowel disease (IBD). Defective apoptosis of inflammatory cell populations seems to be a relevant pathogenetic mechanism in refractory IBD. We assessed the involvement of stress response protein cold-inducible RNA-binding protein (Cirp) in the development of intestinal inflammation and CAC. In the colonic mucosa of patients with ulcerative colitis, expression of Cirp correlated significantly with the expression of TNFα, IL23/IL17, antiapoptotic proteins Bcl-2 and Bcl-xL, and stem cell markers such as Sox2, Bmi1, and Lgr5. The expression of Cirp and Sox2 was enhanced in the colonic mucosae of refractory ulcerative colitis, suggesting that Cirp expression might be related to increased cancer risk. In human CAC specimens, inflammatory cells expressed Cirp protein. Cirp−/− mice given dextran sodium sulfate exhibited decreased susceptibility to colonic inflammation through decreased expression of TNFα, IL23, Bcl-2, and Bcl-xL in colonic lamina propria cells compared with similarly treated wild-type (WT) mice. In the murine CAC model, Cirp deficiency decreased the expression of TNFα, IL23/IL17, Bcl-2, Bcl-xL, and Sox2 and the number of Dclk1+ cells, leading to attenuated tumorigenic potential. Transplantation of Cirp−/− bone marrow into WT mice reduced tumorigenesis, indicating the importance of Cirp in hematopoietic cells. Cirp promotes the development of intestinal inflammation and colorectal tumors through regulating apoptosis and production of TNFα and IL23 in inflammatory cells. Cancer Res; 74(21); 1–10. ©2014 AACR.
