Gastroenterology: The co-activation regulation of ZEB1 and YAP1 zinc dependence plays an important role in pancreatic cancer metastasis

Pancreatic cancer is one of the most severe cancers in the world, with extensive metastasis, and the vast majority of patients are terminally ill at the time of diagnosis.
the plasticity of endothystic intersessional transition (EMT) plays a key role in tumor progression and metastasis by maintaining the transition between EMT and MET states.
this study is to understand the molecular mechanisms that regulate pancreatic cancer metastasis and EMT plasticity.
In human pancreatic cancer cells, clinical samples, spontaneous mouse models (KPC and KPCZ), in-place xeno-transplant models, 3D spherical and organ-like models, the interaction between cancer-promoting zinc finger transporter ZIP4, zinc-dependent EMT transcription factor ZEB1, co-activation factor YAP1 and integrator alpha3 (ITGA3) was observed.
the correlation between ZIP4 and miR-373 and their downstream target genes through RNA in-place hybridization and IHC staining.
chIp, Co-IP, and luciferase were used to report gene testing for transcriptional regulation of ZEP4 to ZEB1, YAP1, and ITGA3.
ZEB1 activates ITGA3 transcription studies through THEP1 binding site on ITGA3 promoter, showing that hippo path effector YAP1 is an effective transcription co-activation factor, which forms a complex with ZEB1 and activates ITGA3 transcription of human pancreatic cancer cells and KPC-sourced mouse cells through THEP1/TEAD binding site.
ZIP4 raises the expression of YAP1 by activating miR-373 and suppressing THEP1 inhibitor LATS2.
ZIP4 enhances cell-ECM adhesion and organ-like formation in addition, ZIP4 upshot promotes EMT plasticity, cell adhesion, sphere and organ-like formation of human pancreatic cancer cells, 3D sphere models, xygen transplant models, and spontaneous mouse models (KPC and KPCZ) via ZEB1/YAP1-ITGA3 signal axis.
, the study shows that ZIP4 activates ZEB1 and YAP1 through different mechanisms.
ZIP4-miR-373-LATS2-ZEB1/YAP1-ITGA3 signal axis has an important effect on the metastasis and EMT plasticity of pancreatic cancer.