NKX3.1 Expression Contributes to Epithelial-Mesenchymal Transition of Prostate Cancer Cells

Iroda Saydullaeva; Bilge Debelec Butuner; Kemal Sami Korkmaz

doi:10.1021/acsomega.3c03127

NKX3.1 Expression Contributes to Epithelial-Mesenchymal Transition of Prostate Cancer Cells

ACS Omega. 2023 Sep 1;8(36):32580-32592. doi: 10.1021/acsomega.3c03127. eCollection 2023 Sep 12.

Authors

Iroda Saydullaeva¹, Bilge Debelec Butuner², Kemal Sami Korkmaz¹

Affiliations

¹ Faculty of Engineering, Department of Bioengineering, Cancer Biology Laboratory, Ege University, Izmir 35040, Turkey.
² Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, Ege University, Izmir 35040, Turkey.

Abstract

Studies demonstrate that inflammation synergizes with high-grade aggressive prostate tumor development and ultimately metastatic spread, in which a lot of work has been done in recent years. However, the clear mechanism of inflammation inciting prostate cancer remains largely uncharacterized. Our previous study has shown that the conditioned media (CM)-mediated LNCaP cell migration is partially correlated with the loss of expression of the tumor suppressor NKX3.1. Here, we continue to investigate the inflammation-mediated migration of prostate cancer cells, and the role of NKX3.1 in this process to gain insights into cell migration-related changes comprehensively. Earlier, the model of inflammation in the tumor microenvironment have been optimized by our research group; here, we continue to investigate the time-dependent effect of CM exposure together with NKX3.1 changes, in which we observed that these changes play important roles in gaining heterogeneous epithelial-to-mesenchymal transition (EMT) phenotype. Hence, this is an important parameter of tumor progression; we depleted NKX3.1 expression using the CRISPR/Cas9 system and examined the migrating cell clusters after exposure to inflammatory cytokines. We found that the migrated cells clearly demonstrate reversible loss of E-cadherin expression, which is consistent with subsequent vimentin expression alterations in comparison to control cells. Moreover, the data suggest that the AR-mediated transcriptional program also contributes to mesenchymal-to-epithelial transition (MET) in prostate cancer progression. Furthermore, the quantitative proteomic analysis showed that migrated subpopulations from the same cell line presented different phenotypes in which the proteins overexpressed are involved in cell metabolism and RNA processing. According to KEGG pathway analysis, the ABC transporters were found to be the most significant. Thus, the dynamic process of cellular migration favors diverse genetic compositions under changing tumor microenvironments. The different levels of invasiveness are supported by shifting the cells in between these EMT and MET phenotypes.