Zinc is an essential cofactor for more than 50 classes of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. Zinc cannot passively diffuse across cell membranes and requires specific transporters, such as SLC39A7, to enter the cytosol from both the extracellular environment and from intracellular storage compartments.[7] The presence of zinc regulates the expression of ZIP transporters.[8]
ZIP7 is involved in controlling glucose metabolism in the skeletal muscle cells by affecting the insulin signaling pathway.[8][10][12] Reduced expression in glucose metabolism genes and proteins such as Glut4, IRS1, IRS2, and Akt phosphorylation occur when ZIP7 mRNA is downregulated.[8][12] When zinc released from ZIP7 binds to PTP1B, the insulin signaling pathway is activated.[12]
There are no experimentally solved structures of ZIP7 in its entirety.[13] ZIP7 has an predicted AlphaFold structure.[13] ZIP7, like other ZIP proteins, has eight transmembrane (TM) helices with a binuclear metal center.[9][10] Two zinc ions bind to residues on TM4 (His329, Asn330, and Asp333) and TM5 (His358, Glu395, and His362).[9][10][13] ZIP proteins are known to make homo- or heterodimeric complexes.[9] The specific mode of transport zinc takes through ZIP transporters has not yet been determined.[9]
ZIP7, a member of the solute carrier family 39 (SLC39) of zinc transporters, emerges as a pivotal factor in cancer progression across multiple malignancies. In breast cancer, ZIP7 expression is markedly elevated in primary tumors, particularly in basal and Her2 subtypes, and correlates with advanced disease stage, metastasis, recurrence, and poorer prognosis. Notably, its hyperactivation is implicated in endocrine resistance, suggesting a crucial role in Endocrine therapy resistance mechanisms.[16][17]
In colorectal cancer, ZIP7 upregulation is observed in tumor tissues compared to normal counterparts. Inhibition of ZIP7 leads to suppressed cell proliferation, colony formation, and enhanced apoptosis, while its heightened presence correlates with adverse patient outcomes, highlighting its significance as a potential prognostic marker.[18][19] Similarly, ZIP7 exhibits elevated expression in cervical cancer tissues, where its knockdown results in inhibited proliferation, migration, and invasion of cancer cells. Furthermore, modulation of epithelial-mesenchymal transition markers underscores ZIP7's involvement in metastatic processes, suggesting its potential as a therapeutic target to impede disease progression.[20] In hepatocellular carcinoma, specific inhibition of ZIP7 attenuates PI3K/AKT signaling, leading to suppressed cell growth, colony formation, migration, invasion, and enhanced apoptosis both in vitro and in vivo. This underscores ZIP7's critical role in hepatocellular carcinoma tumorigenesis and its potential as a therapeutic target in this malignancy.[21]
Moreover, microRNAs play a regulatory role in ZIP7 expression across different cancer types. For instance, in prostate cancer, miR-15a-3p targets ZIP7, leading to the suppression of the Wnt/β-catenin signaling pathway and inhibition of proliferation, invasion, and epithelial-mesenchymal transition. Similarly, in gastric cancer, miR-139-5p negatively regulates ZIP7, inhibiting ZIP7-mediated activation of the Akt/mTOR pathway, thereby suppressing cell proliferation and migration while promoting apoptosis.[22][23]
In a study presented at the 2024 American Association for Cancer Research (AACR) Annual Meeting, researchers introduced rabbit polyclonal antibodies specifically targeting ZIP7 to both human triple-negative breast cancer cells (TNBC) and normal breast epithelial cells (NBE) obtained from the same patient. Utilizing flow cytometry analysis, they observed substantial binding of the ZIP7 antibodies to TNBC cells, while minimal binding was noted in NBE cells from the same individual. Moreover, cytotoxicity assays revealed that the ZIP7-targeted antibodies, in combination with a secondary anti-rabbit Antibody-Drug Conjugate (ADC), selectively induced cell death in TNBC cells over NBE cells. Importantly, this preferential killing effect was attributed to the aberrant surface expression of ZIP7 on TNBC cells, coupled with its involvement in cell proliferation-related signaling pathways specific to TNBC.[24]
In summary, ZIP7 emerges as a critical regulator of cancer progression, influencing key cellular processes such as proliferation, invasion, migration, and apoptosis across various malignancies. Targeting ZIP7 or its regulatory mechanisms holds therapeutic promise in cancer treatment strategies, highlighting its potential as a prognostic marker and therapeutic target in oncology research.
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^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Ando A, Kikuti YY, Shigenari A, Kawata H, Okamoto N, Shiina T, et al. (August 1996). "cDNA cloning of the human homologues of the mouse Ke4 and Ke6 genes at the centromeric end of the human MHC region". Genomics. 35 (3): 600–602. doi:10.1006/geno.1996.0405. PMID8812499.
^Hanson IM, Trowsdale J (Aug 1991). "Colinearity of novel genes in the class II regions of the MHC in mouse and human". Immunogenetics. 34 (1): 5–11. doi:10.1007/BF00212306. PMID1855816. S2CID30046348.
^Sheng N, Yan L, You W, Tan G, Gong J, Chen H, et al. (October 2017). "Knockdown of SLC39A7 inhibits cell growth and induces apoptosis in human colorectal cancer cells". Acta Biochimica et Biophysica Sinica. 49 (10): 926–934. doi:10.1093/abbs/gmx094. PMID28981607.
^Wei Y, Dong J, Li F, Wei Z, Tian Y (2017). "Knockdown of SLC39A7 suppresses cell proliferation, migration and invasion in cervical cancer". EXCLI Journal. 16: 1165–1176. doi:10.17179/excli2017-690. PMID29285013.
^Cui Y, Yang Y, Ren L, Yang J, Wang B, Xing T, et al. (September 2019). "miR-15a-3p Suppresses Prostate Cancer Cell Proliferation and Invasion by Targeting SLC39A7 Via Downregulating Wnt/β-Catenin Signaling Pathway". Cancer Biotherapy & Radiopharmaceuticals. 34 (7): 472–479. doi:10.1089/cbr.2018.2722. PMID31135177.
^Manavalan JS, Mor D, Davis J, Saini S, Pal I, Feith D, et al. (22 March 2024). "Abstract 4109: Discovery of a novel cancer-specific antigen for therapeutic targeting using the Oncotope platform". Cancer Research. 84 (6_Supplement): 4109. doi:10.1158/1538-7445.AM2024-4109.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Kim JE, Tannenbaum SR, White FM (2005). "Global phosphoproteome of HT-29 human colon adenocarcinoma cells". Journal of Proteome Research. 4 (4): 1339–1346. doi:10.1021/pr050048h. PMID16083285.