| First Author | Kuo CY | Year | 2017 |
| Journal | Cancer Res | Volume | 77 |
| Issue | 13 | Pages | 3406-3416 |
| PubMed ID | 28533271 | Mgi Jnum | J:243202 |
| Mgi Id | MGI:5907916 | Doi | 10.1158/0008-5472.CAN-16-3196 |
| Citation | Kuo CY, et al. (2017) VHL Inactivation in Precancerous Kidney Cells Induces an Inflammatory Response via ER Stress-Activated IRE1alpha Signaling. Cancer Res 77(13):3406-3416 |
| abstractText | Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss of function in the development of ccRCC via inflammation remains poorly understood. VHL-mutant cells exhibit metabolic abnormalities that can cause chronic endoplasmic reticulum (ER) stress and unfolded protein response. We hypothesize that unresolved ER stress induces the inflammatory responses observed in ccRCC. ER stress markers including BiP and XBP1s were significantly increased in cultured and primary VHL loss-of-function kidney cells. In epithelial cells, the kinase activity of IRE1alpha was required for the induction of NF-kappaB and JNK and for the recruitment of macrophages. IRE1alpha kinase activity was also important for the development of fibrotic phenotype in conditional Vhlh knockout mice. Our results offer insights into the therapeutic potential against ccRCC development by relieving metabolic stress. Such cancer prevention strategy may be critical for high-risk cohorts such as the familial VHL disease patients. Cancer Res; 77(13); 3406-16. (c)2017 AACR. |
