For PCa, the primary treatment is ADT. When it comes to CRPC, docetaxel chemotherapy is a standard approach, showing significant symptomatic and survival benefits[11, 13]. However, docetaxel resistance in CRPC patients usually occurs after approximately six months of systemic therapy. Multiple mechanisms have been reported to be involved in drug resistance, such as limiting intracellular drug concentrations, impaired drug-induced microtubules stability, and neutralizing cytotoxic effects [22–26]. Therefore, targeting drug-resistance and prognosis-related genes has the potential to improve chemotherapy and survival. The aim of this study was to identify and analyze the functions of hub prognostic genes to help understand the molecular mechanisms underlying the development of DCRPC and to provide novel gene targets for future studies.
After a systematic search, two microarray datasets were included. In GSE33455 and GSE31635, PCa cell lines were converted to docetaxel-resistant cells to compare the gene expression profile of sensitive and resistant cells. To improve the reliability of our results, we performed batch normalization on both datasets before identifying DEGs. Finally, 89 DEGs were identified, of which 47 genes were up-regulated and 42 genes were downregulated. In order to further investigate the functions of these DEGs, we performed a series of bioinformatic analyses.
The cellular mechanism of drug resistance can be generally divided into two categories: inhibition of chemotherapeutic drug delivery to tumor cells and increased genetic and epigenetic alterations affecting drug sensitivity [27]. GO functional analysis had showed that these DEGs were mainly enriched in the extracellular exosome, cell adhesion molecule binding, ATP binding and cellular response to tumor necrosis factor (TNF). Exosomes can serve as effective carriers of chemotherapeutic drugs [28, 29]. However, in drug-resistant cancer cells, this mechanism is blocking, which may lead sensitive cells to drug-resistance [30]. Several studies had identified a role for exosomes in chemotherapy resistance through induction of epithelial mesenchymal transformation (EMT); promotion of antiapoptotic pathways; drug efflux or sequestration; alerted signal transduction and immune cell regulation [31–36]. Cell adhesion molecules (CAMs) are in involved in tumor progression, metastasis. Expression of CD44, a member of the CAMs family, could increase drug efflux and lead to drug-resistance [37]. Targeting CAMs has been reported to inhibit metastasis and drug-resistance [38]. In addition, ATP-binding cassette (ABC) transporters have been reported to be drug-resistance proteins. P-glycoprotein (P-gp), a product of the ABCB1 gene, is an ATP dependent efflux pump that increases drug efflux when substrates are bound to transmembrane regions [39]. TNF plays an important role in cellular autophagy. Previous study found that TNF signaling could promote paclitaxel-resistance in ovarian cancer by inducing autophagy [40]. In addition, TNF inhibitor was also reported to overcome drug-resistance to anti-PD-1 treatment [41].
KEGG pathway analysis revealed that these DEGs are mainly involved in the TNF signaling pathway, chemokine pathway, and nicotinate and nicotinamide metabolism. Several chemokines were found to be highly overexpressed in oxaliplatin-resistant in the HTOXAR3 cell line, however, gene silencing resulted in a slight reversal of resistance [42]. Furthermore, targeting CXCL2 (a chemokine receptor) in taxane-exposed mCRPC model resulted in PCa cells being sensitive to cisplatin [43]. Nicotinamide (NAM) is a vitamin B3 derivative and a precursor of nicotinamide adenine dinucleotide (NAD+). Nicotinamide metabolism is essential for a variety of biological functions in human cells, such as: cellular metabolic processes and DNA repairing [44, 45]. Nicotinamide derivatives have been reported to be effective in reversing P-gp-induced drug-resistance by inhibiting the efflux function [46, 47].
In this study, we identified four prognostic hub genes, RHOF, ADCY7, DOCK2 and LMO7. RHOF is a member of the Rho GTPase family, an oncogene that plays an important role in tumor cell invasion and migration. High expression of RHOF is closely associated with tumor progression and poor survival of patients [48, 49]. Yang et al. found that targeting RHOF could improve the sensitivity of pancreatic cells to gemcitabine treatment through the EMT pathway [49].
Adenylate cyclase 7 (ADCY7) is a member of enzymes involved in ATP metabolism and cAMP production. Although the molecular mechanism of ADCY7 in drug-resistance is not clear. However, ADCY7 has been reported to be involved in inflammatory responses and TNF-α signaling pathway [50], which could be a potential association between ADCY7 and chemotherapy resistance.
DOCK2 (dedicator of cytokinesis 2) is a Rac-specific guanine nucleotide exchange factor for Rho GTPases. Previous studies had demonstrated the role of DOCK2 in cell proliferation, migration and invasion and DNA damage response [51, 52]. Wu et al. found that targeting DOCK2 improved the sensitivity of leukemia cells to chemotherapy by modulating DNA repairing pathway [53].
LIM domain only protein 7 (LMO7) is a fibrous actin-binding protein that belongs to PDZ and LIM domain‐containing protein family and functions as protein–protein recognition modules [54]. LMO7 was found to be located in cell membrane, cytoskeleton and intracellular nucleus and is involved in cell invasion and migration [55, 56]. LMO7 deficiency leads to enhanced TGF-β signaling pathway and exacerbates extracellular matrix (ECM) deposition [57]. In mice model, lung cancer was found in 22% of LMO7(-/-) mice compared to only 13% of LMO7(+/-) mice [54]. Previous study had also shown that targeting LMO7 lead to drug-resistance [58].
In summary, GO and KEGG enrichment analysis confirmed the functions and pathways of DEGs. In addition, our study identified RHOF, ADCY7, DOCK2 and LMO7 as prognostic hub gene. Although several studies had been conducted to investigate these gens, the mechanism of CRPC docetaxel-resistance is not clear. The present study will contribute to the understanding of the molecular mechanism of DCRPC development and provide new gene targets for future studies.