Taken together, our results demonstrate that USP10 is a critical regulator of KLF4, pinpointing USP10-KLF4-TIMP3 axis as a promising therapeutic target in lung cancer.
Mechanistic studies indicated that TIMP-3 overexpression reduced NF-κB activity, which led to cell growth inhibition in IL-32γ transfected lung cancer cells.
Immunohistochemistry showed that the expression of miR-222 in lung cancer tissue was significantly higher, but TIMP3 was lower than that in normal lung tissue (<i>P</i> = 0.0001 for the former and <i>P</i> = 0.0002 for the latter).
For TIMP3, males showed lower methylation frequency than females (OR=0.18, 95%CI=0.04-0.88) while central lung cancer, heavy smoking and radiation exposure presented higher aberrant DNA methylation status (OR=2.19, 95%CI=1.07-4.52; OR=6.99, 95%CI=1.32-37.14; OR=2.30, 95%CI=1.04-5.08).
In addition, electrophoretic mobility shift and chromatin immunoprecipitation assays show that Sp1 transcription factor mediated Ad-MMP-2-Si-CM-stimulated increase of TIMP-3.