Fig. 6
The molecular mechanism of zinc transporters and MTs in PC. ZIP4 promotes PC carcinogenesis mainly through two transcription factors, CREB and ZEB1. ZEB1 promotes the procession of EMT by suppressing the expression of ZO-1 and CLDN1 and inducing the transcription of ITGA3. Moreover, the ZEB1 induces integrin α3β1 to phosphorylate JNK and ultimately blocks ENT1, a gemcitabine transporter, which results in chemoresistance. Besides, cellular zinc released by MT1G inhibits NF-κB, suppressing PC chemoresistance. CREB transcripts miR-373 to increase metastasis, invasion, and proliferation by activating the Hippo pathway yet inhibiting the expression of TP53INP1 and CD44. Besides, PHLPP2, inhibited by miR-373, forms a malignant cycle through the suppression of CREB. However, the small molecule, circ ANAPC7, can block miR-373. As a target for PHLPP2 dephosphorylation, AKT increases the proliferation by upregulating cyclin D1 and promotes muscle wasting by phosphorylating STAT5. Another CREB-mediated downstream promoting muscle wasting is RAB27B. Mechanically, RAB27B promotes the release of HSP70 and HSP90 from MVB. Additionally, the CREB-mediated IL-6/STAT3/cyclin D1 pathway leads to proliferation in PC. ZIP4 could restrain apoptosis by inhibiting the activity of caspase9 and caspase7. The expression of ZIP3 is reduced by RREB-1. ZO-1, zonula occludens-1; ITGA3, integrin subunit alpha 3; JNK, c-Jun N-terminal kinase; MVB, multivesicular body; EMT, epithelial-mesenchymal transition
