Zinc oxide nanoparticle attenuates chemotherapy resistance by inducing cell stemness progression of colorectal cancer via miR-1321/HIF-2a axis

Background: Colorectal cancer (CRC) is the most malignant cancer type with high morbidity and mortality worldwide. Developed drug resistance severely affected the prognosis of CRC patients. This work aimed to explore the effects of zinc oxide nanoparticles (ZONs) in chemoresistant CRC. Methods: We established Oxaliplatin (Oxa)-resistant CRC cells, and in vitro and in vivo model to evaluate the function effect of ZONs. Cell counting kit-8 (CCK-8), colony formation, and 5-ethynyl-2'-deoxyuridine (EDU) assay were performed to detect CRC cell viability and proliferation. CRC cell apoptosis was checked by flow cytometry. Tumor cell proliferation was checked by immunohistochemistry (IHC). Cell stemness was determined by sphere formation assay. Luciferase reporter gene assay was conducted to assess the binding of miR-1321 and HIF-2 alpha 3'UTR region. Results: ZONs suppressed the viability and proliferation of Oxa-resistant CRC cells both in vitro and in vivo. ZONs suppressed CRC cell stemness and enhanced the sensitivity of CRC cells to chemo-therapy, along with decreased expression of stem cell biomarkers. ZONs elevated level of miR-1321 and reduced level of HIF-2 alpha in CRC cells. MiR-1321 targeted the 3'UTR region of HIF-2 alpha to suppress its expression. ZONs repressed HIF-2 alpha expression by inducing miR-1321 in CRC cells. Conclusion: ZONs treatment remarkably converted the drug resistance and stemness of CRC cells, via upregulating miR-1321 to repress the expression of HIF-2a. Our findings suggested that ZONs are potential and effective agent for chemo-resistant CRC patients. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of King Saud University.