Abstract
BACKGROUND: Autophagy-related proteins (ATGs) regulate a great variety of cellular responses beyond autophagy. In cancer, the role of ATG proteins is central, as evidenced in spontaneous cancer emerging in animals lacking ATG proteins. AIM: To determine whether ATG16L1 may be participating in tumorigenesis in colonic and oral mucosa and its likely association with adaptive immune cell deregulation (e.g., B cells). METHODS: Wild-type (WT) and ATG16L1 hypomorphic mice (ATG16L1(HM)) were induced with colitis-associated colon cancer (CAC) by delivering azoxymethane (AOM) and dextran sodium sulfate (DSS), whereas oral cancer was generated by administering 4-nitroquinoline-1-oxide (4NQO) in tap water. Tissue samples were collected and the histopathological damage was assessed. Also, secondary lymphoid organs (i.e., spleen and draining lymph nodes) were assayed for cytokine output and lymphocyte distribution by means of flow cytometry, and IgG levels were assayed in plasma samples. RESULTS: ATG16L1(HM) animals turned out to be more susceptible to colon and oral carcinogenesis than WT mice. In CAC, WT mice preserved colon length and presented individual colonic tumors, whereas ATG16L1(HM) mice presented shortened colons and tumor masses. Likewise, WT mice exhibited oral leukoplakia (pre-neoplastic lesions), whereas ATG16L1(HM) mice showed tumors. The greater susceptibility observed in ATG16L1(HM) animals was associated with imbalanced cytokine production (increased IL-4 levels and lower IL-15 output) and higher numbers of B cells in secondary lymphoid organs. This latter was also found under steady conditions, and despite having more B cells, cancer-induced ATG16L1(HM) mice presented lower levels of total circulating IgG. CONCLUSION: Suboptimal expression of the autophagic protein ATG16L1 results in accelerated carcinogenesis, and an altered B cell response may be one of the aggravating factors.