Bcl-xL is an oncogenic driver in colorectal cancer

摘要: Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family mainly known for its pivotal role regulation of mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits induce therapy resistance cells. Among anti-apoptotic proteins, we found solely Bcl-xL strongly upregulated human CRC specimens. In order to study function context tumor initiation progression vivo, generated a mouse model lacking intestinal epithelial cells (Bcl-xL(IEC-KO)). If challenged an inflammation-driven model, Bcl-xL(IEC-KO) mice showed significantly reduced burden with lower numbers per animal decreased sizes. Analysis cell events by immunohistochemistry immunoblotting revealed striking increase apoptosis Bcl-xL-negative tumors. qRT-PCR excluded changes proliferative capacity immune infiltration as reasons load thereby identify key mechanism. Human tissue was cultured ex vivo treated small molecule compound ABT-737, which inhibits Bcl-2. Under ABT-737 treatment, amount apoptotic increased compared controls, whereas proliferation levels remained unaltered. summary, our findings driver colorectal tumorigenesis progression, making it valuable target clinical application.