Zinc dyshomeostasis in azoxymethane induced colonic precancerous and cancerous lesions in Fisher rats
Abstract Zinc is an essential micronutrient involved in various biological processes, including growth, maintenance, proliferation and immune functions. It is also argued that tumors need zinc for maintenance and proliferation, although excess zinc may induce tumor cell apoptosis. Thus, the role of zinc merits attention in the carcinogenic process. Scanty literature is available on the mechanisms underlying the alterations in tissue zinc in colon cancer and how the altered zinc levels contribute to the preneoplastic lesions and progression to cancer. Zinc homeostasis is regulated by the gastrointestinal tract and involves interplay of host, dietary, environmental and social factors such as alcohol consumption. The DNA alkylation agent azoxymethane (AOM), which is primarily activated in the liver, induces a high incidence of initiation and promotion steps of precancerous lesions in the colon of rats. The altered expression of hepatic zinc transporters by AOM may lead to zinc dyshomeostasis in liver. Earlier reports showed that ZIP14 was located on the inner lane of plasma membrane of hepatocytes, and increased level of ZIP14 could sequester zinc from plasma into liver under infection or in response to cancer. Decreased serum zinc concentration, despite increased liver zinc also indicates altered liver zinc mobilization and failure to regulate zinc homeostasis. During the transformation from normal colonic mucosa to colonic epithelial hyperplasia and aberrant crypt formation, a reduction in zinc concentration is observed. It will be interesting to study further if the same trend continues throughout tumor progression towards adenocarcinomas. Lowered local zinc concentrations in the colon epithelium may not just reflect a bystander effect, but may induce cell proliferation and compromise DNA integrity due to impairment of zinc-containing proteins. In congruence with the tissue zinc concentrations, metallothionein levels were found to be less induced in AOM—administered colon compared to normal healthy colon, indicating less accumulation and sequestration of zinc. Lowered tissue zinc levels in small and large intestine were also associated with increased expression of mRNA and protein ZnT1, known to transport cytosolic zinc to extracellular space. In this regard, the mode of zinc responsiveness to ZnT1 mimics that of metallothionein, albeit at a lower level for ZnT1.