Reduced Expression of Mismatch Repair Genes MSH6/MSH2 Directly Promotes Pituitary Tumor Growth via the ATR–Chk1 Pathway

The mechanisms of pituitary adenoma (PA) pathogenesis and proliferation remain largely unknown. To evaluate the direct association between PA proliferation and expression of mismatch repair (MMR) genes and proteins, and to clarify the role of MMR genes in the molecular mechanism of PA proliferation. We performed quantitative analyses by real-time PCR and immunohistochemistry to detect MMR gene and protein expression in human PAs (n = 47). We also performed correlation analyses of expression levels and tumor volume doubling time (TVDT) (n = 31). Specifically, correlation analyses were performed between genes with significant correlation and ATR expression in cell-cycle regulatory mechanism ATR-Chk1 pathway (n = 93). We investigated the effect of reduced gene expression on cell proliferation and ATR gene expression in AtT-20ins cells and primary cultures of human PAs. Expression of MSH6 and MSH2 was positively associated with TVDT (R = 0.52, P = 0.003 and R = 0.44, P = 0.01), as were the corresponding protein levels. Gene expression was positively associated with ATR expression (R = 0.47, P < 0.00001 and R = 0.49, P < 0.00001). In AtT-20ins, the reduction of MSH6 and/or MSH2 expression by siRNA significantly promoted cell proliferation by decreasing ATR expression. This effect was also observed in primary culture. Reduction of MSH6 and MSH2 expression at the mRNA and protein levels could be involved in direct PA proliferation by promoting cell-cycle progression or decreasing the rate of apoptosis through interference with the function of the ATR-Chk1 pathway.