Radioresistance is still a huge obstacle of colon cancer treatment, although the effectiveness of some new radiotherapy technologies, such as selective internal radiotherapy and stereotactic body radiotherapy, have been confirmed.[4, 18, 19] The exploration of radioresistance mechanisms could provide strategies for improving the efficacy of radiotherapy.[5] The results of information analyses of databases and IHC staining showed that ZIP7 was highly expressed in colon cancer tissues, indicating it may be a therapeutic target.
Zinc is an important signal mediator in the progression of various tumors, and plays key roles in many malignant biological behaviors. Cheng et al. confirmed that zinc supplementation could significantly increase the metastasis and invasion abilities of esophageal cancer cells, which effects were effectively reversed by zinc chelator TPEN.[20] And these phenomena may attribute to zinc activated PI3K/AKT and MAPK/ERK signaling pathway.[20] In addition, it has been reported that TPEN could cause cell death in a dose-dependent manner by inducing oxidative stress and inhibiting autophagy, and zinc application completely reversed this kind of death.[21] For tumor radiotherapy, autophagy plays a cytoprotective role. In glioma cells, the chelation of intracellular zinc blocked the lysosomal degradation of autophagic vesicles, and further reduced the survival fraction of cells in radiotherapy. However, the equivalent dose of TPEN has no effect on glioma cells without radiotherapy.[22] In this study, we found that low concentration TPEN significantly reversed the radioresistance of progeny colon cancer cells, which provides a theoretical basis for the application of TPEN in colon cancer radiotherapy.
The impact of ZIP7 on some malignant biological behaviors of cancer has been reported, including breast cancer, cervical cancer and gastric cancer.[13–15] Sheng et al. found that downregulation of ZIP7 significantly inhibited cell growth and induced apoptosis in colon cancer cells.[23] However, little is known about the role of this molecule in cancer radioresistance. In this study, knockdown ZIP7 was found could significantly reduce the survival ability of radioresistant colon cancer cells after irradiation, while transmembrane ionophore of zinc partially reversed this effect. This result indicated that ZIP7 kept colon cancer radioresistance through regulation of zinc.
ZIP7 has been considered to be “a hub for tyrosine kinase activation”.[12] In the progression of cancer, some major pathways, such as MAPK, PI3K-AKT and mTOR, could be actived by ZIP7-mediated zinc release from intracellular stores.[24] Other members of ZIPs family have also been confirmed to promote tumor development through the above signaling pathways.[7, 20] In addition, ZIP7 plays an important role in maintenance the function state of endoplasmic reticulum (ER). Knockdown or knockout the expression of ZIP7 could induce ER stress and impact protein transport.[25–27] Therefore, the influence of ZIP7 on colon cancer radioresistance, as verified in this study, may be completed through a complex network.
For basic mechanisms, EMT acting as an essential process involved in acquired radioresistance has been widely accepted.[28] Irradiation can induce the occurrence of EMT through many signaling pathways. [28] During EMT, not only the interactions of cell-cell and cell-extracellular matrix are remodeled, but also the cancer stem cell properties, enhanced DNA damage response and antioxidant activity abilities are obtained.[29, 30] In this study, we found that irradiation induction promoted ZIP7 and ZEB1 expression, and the occurrence of EMT. Knockdown of ZIP7 could downregulate ZEB1 expression, but upregulate E-cadherin expression, and both of which could be partially reversed by Py treatment. These results indicated that ZIP7, through regulation of zinc, kept colon cancer radioresistance at least partially by maintenance of EMT. Therefore, ZIP7 may be a novel druggable node in radiosensitization treatment of colon cancer, and this could be possible because a small molecule inhibitor of ZIP7 has been developed.[31]