Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization
| Autor: | Ryan H. Moy, Alexander Nguyen, Jia Min Loo, Norihiro Yamaguchi, Christina M. Kajba, Balaji Santhanam, Benjamin N. Ostendorf, Y. Gloria Wu, Saeed Tavazoie, Sohail F. Tavazoie |
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| Rok vydání: | 2022 |
| Předmět: |
colorectal cancer
RELB Medical and Health Sciences Article General Biochemistry Genetics and Molecular Biology Genetics metastasis Humans Inositol 1 4 5-Trisphosphate Receptors Molecular Biology 5-Trisphosphate Receptors Cancer calcium hypoxia Liver Disease Prevention Liver Neoplasms Transcription Factor RelB ITPR3 NF-kappa B Cell Biology Biological Sciences Inositol 1 non-canonical NF-κB Colo-Rectal Cancer Calcium Digestive Diseases Colorectal Neoplasms Developmental Biology |
| Zdroj: | Dev Cell Developmental cell, vol 57, iss 9 |
| ISSN: | 1534-5807 |
| Popis: | Metastatic colonization is the primary cause of death from colorectal cancer (CRC). We employed genome-scale invivo short hairpin RNA (shRNA) screening and validation to identify 26 promoters of CRC liver colonization. Among these genes, we identified a cluster that contains multiple targetable genes, including ITPR3, which promoted liver-metastatic colonization and elicited similar downstream gene expression programs. ITPR3 is a caffeine-sensitive inositol 1,4,5-triphosphate (IP3) receptor that releases calcium from the endoplasmic reticulum and enhanced metastatic colonization by inducing expression of RELB, a transcription factor that is associated with non-canonical NF-κB signaling. Genetic, cell biological, pharmacologic, and clinical association studies revealed that ITPR3 and RELB drive CRC colony formation by promoting cell survival upon substratum detachment or hypoxic exposure. RELB was sufficient to drive colonization downstream of ITPR3. Our findings implicate the ITPR3/calcium/RELB axis in CRC metastatic colony formation and uncover multiple clinico-pathologically associated targetable proteins as drivers of CRC metastatic colonization. |
| Databáze: | OpenAIRE |
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