Hyperactivated YAP1 is essential for sustainable progression of renal clear cell carcinoma
Xiangmin Lv1, Jiyuan Liu1, Kazi Islam1
1Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Abstract:
The most notable progress in renal clear cell carcinoma (ccRCC) in the past decades is the introduction of drugs targeting the VHL-HIF signaling pathway-associated angiogenesis. However, mechanisms underlying the development of VHL mutation-independent ccRCC are unclear. Here we provide evidence that the disrupted Hippo-YAP signaling contributes to the development of ccRCC independent of VHL alteration. We found that YAP1 and its primary target genes are frequently upregulated in ccRCC and the upregulation of these genes is associated with unfavorable patient outcomes. Research results derived from our in vitro and in vivo experimental models demonstrated that, under normoxic conditions, hyperactivated YAP1 drives the expression of FGFs to stimulate the proliferation of tumor and tumor-associated endothelial cells in an autocrine/paracrine manner. When rapidly growing cancer cells create a hypoxic environment, hyperactivated YAP1 in cancer cells induces the production of VEGF, which promotes the angiogenesis of tumor-associated endothelial cells, leading to improved tumor microenvironment and continuous tumor growth. Our study indicates that hyperactivated YAP1 is essential for maintaining ccRCC progression, and targeting the dual role of hyperactivated YAP1 represents a novel strategy to improve renal carcinoma therapy.
Insights
Disrupted Hippo-YAP signaling drives clear cell renal cell carcinoma (ccRCC) independent of VHL mutations. Hyperactivated YAP1 promotes tumor growth and angiogenesis, offering a new therapeutic target for ccRCC.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Clear cell renal cell carcinoma (ccRCC) treatments often target VHL-HIF pathway-associated angiogenesis.
- Mechanisms of VHL mutation-independent ccRCC remain largely unknown.
- The Hippo-YAP signaling pathway's role in ccRCC is under investigation.
Purpose of the Study:
- To investigate the role of Hippo-YAP signaling in VHL-independent ccRCC development.
- To determine the association between YAP1 upregulation and patient outcomes in ccRCC.
- To elucidate the mechanisms by which hyperactivated YAP1 drives ccRCC progression.
Main Methods:
- Analysis of YAP1 and its target gene expression in ccRCC tissues.
- In vitro and in vivo experimental models of ccRCC.
- Investigation of YAP1's role under normoxic and hypoxic conditions.
Main Results:
- YAP1 and its target genes are frequently upregulated in ccRCC, correlating with poor patient outcomes.
- Hyperactivated YAP1 promotes tumor and endothelial cell proliferation via FGF signaling under normoxia.
- Hyperactivated YAP1 induces VEGF production under hypoxia, promoting angiogenesis and tumor growth.
Conclusions:
- Disrupted Hippo-YAP signaling contributes to VHL-independent ccRCC.
- Hyperactivated YAP1 is crucial for ccRCC progression by driving proliferation and angiogenesis.
- Targeting hyperactivated YAP1 presents a novel therapeutic strategy for renal carcinoma.
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