Lymphocytic infiltration of the salivary glands in autoimmune diseases results in the human condition known as xerostomia. To date, an animal model for the autoimmune development of salivary gland dysfunction has yet to be described. With the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain, salivary flow rates and total saliva protein concentration in both male and female mice showed a progressive decline in the nondiabetic and diabetic states. Submandibular gland weight decreased from control mice with the progression to onset of diabetes in both sexes, whereas the weight of the parotid gland remained unchanged. The level of saliva amylase activity, when measured relative to unit volume, decreased in nondiabetic males but increased upon onset of diabetes to control values. When expressed relative to protein concentration in saliva, amylase activity was depressed for both sets of NOD mice but was higher upon diabetes onset than in the nondiabetic animals. In females a similar pattern was observed except that amylase activity expressed relative to unit volume was not significantly depressed in either set of NOD mice. The same observations were made for glandular amylase activity. The level of epidermal growth factor (a product of the ductal cells of the submandibular gland) was reduced over 500- and 18-fold for male and female diabetic mice, respectively. Sodium dodecyl sulfate polyacrylamide gels of total saliva showed changes in mobility as well as concentration of several proteins in the NOD mice.(ABSTRACT TRUNCATED AT 250 WORDS)

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Colorectal cancer (CRC) is a type of cancer with a mortality rate among the highest worldwide owing to its high rate of metastasis. Therefore, inflammation-associated metastasis in the development of CRC is currently a topic of considerable interest. In the present study, the pro-inflammatory cytokine interleukin-4 (IL-4) was identified to promote the epithelial-mesenchymal transition (EMT) of CRC cells. However, the enhancing effect of IL-4 was more evident in HCT116 cells compared with in RKO cells. Accordingly, an increased expression level of STAT6 was observed in HCT116 cells compared with RKO cells. Further investigations identified that E2F1 was required for maintaining the level of signal transducer and activator of transcription 6 (STAT6) in HCT116 cells. Mechanistically, E2F1 induced specificity protein 3 (SP3) directly by binding to the promoter of the STAT6 gene and activating its transcription in CRC cells. As a result, phosphorylation-activated STAT6 increased the expression of several EMT drivers, including zinc finger E-box-binding homeobox (Zeb)1 and Zeb2, which serve a critical function in IL-4-induced EMT. Rescue experiments further confirmed that IL-4-induced EMT relied on an intact E2F1/SP3/STAT6 axis in CRC cells. Finally, analysis of clinical CRC specimens revealed a positive correlation between E2F1, SP3 and STAT6. The ectopically expressed E2F1/SP3/STAT6 axis indicated a poor prognosis in patients with CRC. In conclusion, the E2F1/SP3/STAT6 pathway was identified to be essential for IL-4 signaling-induced EMT and aggressiveness of CRC cells.

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