Perineural invasion in prostate cancer is associated with Schwann cells and disruption of circadian rhythm-related gene expression: A bioinformatics approach

Abstract

Schwann cells in the tumor microenvironment are reportedly involved in the production of several factors that benefit cancer cell growth. During this process, Schwann cells are dedifferentiated and facilitate cancer cellular proliferation. The cells then migrate to the region close to the tumor tissue and assist the development of the neoplastic cells. Accordingly, the present study was designed to evaluate the perineural invasion in prostate cancer, in association with disrupted circadian rhythm-related gene expression in Schwann cells. Initially, we identified a database reporting gene expression in Schwann cells in a neoplastic context from the GEO Datasets platform in the GEO repository. The database contains the expression results from experiments in which two factors produced by tumor cells were added to cell cultures. Comparisons were made between samples from the first and third passages. Then, these data were used in differential gene expression analysis and combined with differential expression data of genes upregulated in perineural invasion-negative and -positive prostate cancers. We observed that the “axon guidance” pathway was upregulated in perineural invasion-negative prostate cancers. Meanwhile, upregulated mRNAs activated the “axon guidance” pathway and, together with ROBO1 and MPZ upregulation, inhibited perineural invasion pathways. Both genes are also associated with inhibition of Schwann cell migration. PER3, NR3C1, PPARGC1A, TIMP3, ID2, PDE6B, and CAVIN1 were upregulated in perineural invasion-negative tumors, while SLC25A10 was upregulated. We also observed upregulated expression in perineural invasion-positive tumors for genes such as PPARGC1A, TIMP3, S100A8, ID2, DEFB1, AQP3, ASS1, PDE6B, NEFH, and CAVIN1. AQP3 and NEFH were upregulated only in perineural invasion-positive tumors and PER3 and NR3C1 were upregulated only in perineural invasion-negative samples. The findings revealed that circadian rhythm and/or melatonin disruption are associated with dedifferentiation of Schwann cells, which consequently produce a set of factors that drive tumor progression. These processes may also be involved in tumor invasion into the perineural tissue in prostate cancer.