Fig. 7
The molecular mechanism of zinc transporters and metallothioneins in CRC, GC, and ESCC. In CRC, the binding of ZnT9 and β-catenin triggers the transcription of CCND1, MYC, and MMP7, resulting in proliferation and migration. KCTD9 can replace the binding of ZnT9 and β-catenin. Moreover, ZIP14 contains two alternative splicings, ZIP14-4A and ZIP14-4B. ZIP14-4B is upregulated by SRPK1 and SRSF1, two downstream targets of Wnt signaling, leading to increased Cd2+ uptake. Concerning the GC microenvironment, ZIP7 is the upstream target of the AKT/mTOR signaling pathway. In GC, autophagic degradation of MT1E, MT1M, and MT1X initiated by USP2-E2F4 interaction leads to increased intracellular zinc storage vesicles, promoting GC cell growth. In contrast, MT2A inhibits NF-κB by releasing cellular zinc and thus ultimately suppresses GC cell proliferation. As for ESCC, ZIP6 activates PI3K/AKT and MAPK/ERK signaling pathways, which leads to the overexpression of downstream oncogenes such as MMP1, MMP3, MYC, and SLUG. Meanwhile, the cellular zinc released by MT2A promotes the oncogenic function of IGFBP2. NF-κBIA, NF-κB inhibitor alpha; IGFBP2, insulin-like growth factor binding protein 2
