Nuclear adenomatous polyposis coli suppresses colitis-associated tumorigenesis in mice

Mutation of tumor suppressor adenomatous polyposis coli (APC) initiates most colorectal cancers and chronic colitis increases risk. APC is a nucleo-cytoplasmic shuttling protein, best known for antagonizing Wnt signaling by forming a cytoplasmic complex that marks β-catenin for degradation. Using our unique mouse model with compromised nuclear Apc import (ApcmNLS), we show that ApcmNLS/mNLS mice have increased susceptibility to tumorigenesis induced with azoxymethane (AOM) and dextran sodium sulfate (DSS). The AOM–DSS-induced colon adenoma histopathology, proliferation, apoptosis, stem cell number and β-catenin and Kras mutation spectra were similar in ApcmNLS/mNLS and Apc+/+ mice. However, AOM–DSS-treated ApcmNLS/mNLS mice showed more weight loss, more lymphoid follicles and edema, and increased colon shortening than treated Apc+/+ mice, indicating a colitis predisposition. To test this directly, we induced acute colitis with a 7 day DSS treatment followed by 5 days of recovery. Compared with Apc+/+ mice, DSS-treated ApcmNLS/mNLS mice developed more severe colitis based on clinical grade and histopathology. ApcmNLS/mNLS mice also had higher lymphocytic infiltration and reduced expression of stem cell markers, suggesting an increased propensity for chronic inflammation. Moreover, colons from DSS-treated ApcmNLS/mNLS mice showed fewer goblet cells and reduced Muc2 expression. Even in untreated ApcmNLS/mNLS mice, there were significantly fewer goblet cells in jejuna, and a modest decrease in colonocyte Muc2 expression compared with Apc+/+ mice. Colonocytes from untreated ApcmNLS/mNLS mice also showed increased expression of inflammatory mediators cyclooxygenase-2 (Cox-2) and macrophage inflammatory protein-2 (MIP-2). These findings reveal novel functions for nuclear Apc in goblet cell differentiation and protection against inflammation-induced colon tumorigenesis.