According to estimates from the GLOBOCAN, an estimated 129079 newly diagnosed cases of NPC and 72987 patients die of this neoplasm were reported for 2018 worldwide . Etiologic factors for NPC include genetic, ethic, EBV infection, and environmental factors [4–8]. Despite substantial improvement in treatment for NPC during the past decade, patients with NPC diagnosis and prognosis remains largely unsatisfactory due to lack of obvious clinical signs in its early stages and most of them were late stages at the time of clinical discovery . Therefore, to reveal the molecular mechanism of NPC is great significance.
In our study, WGCNA was applied to identify potential molecular biomarkers and small-molecule drugs associated with the progression of NPC patients. We totally found 430 DEGs and 11 co-expressed gene modules through WGCNA analysis. The green module had the greatest correlation with NPC tumor stage. Four genes were identified as the final hub genes, which had high functional significance in the clinically significant module. Compared with normal tissues, PGAP1, MARK1, and KITLG were significantly higher expression in patients with NPC, while CRIP1 was significantly lower expression in patients with NPC in both test and validation datasets. Meanwhile, the results of ROC analysis showed that these four hub genes have excellent diagnostic efficiency for tumor and normal tissues. Furthermore, functional enrichment analysis showed that green module genes were mainly enriched in cellular response to nutrient levels, regulation of cell cycle process, and p53 signaling pathway.
PGAP1, the gene encoding the post-GPI attachment to proteins 1, which is closely associated with cell cycle process, cell proliferation, cell differentiation, and multiple signaling transduction pathways. PGAP1 can directly and/or indirectly induce carcinogenesis by tumor cell proliferation, migration, and multiple drug resistance [24–27]. MARK1, also known as partitioning defective gene 1 (Par-1), is a member of the family of serine-threonine kinases, which plays a vital role in the regulations of cell migration, cell proliferation, establishing and maintaining cell polarity, and microtubule [28–30]. Several research results revealed that MARK1 plays an important role in tumorigenesis, Natalia et al. found that MARK1 was a novel functional target for miR-125a-5p with implications on the regulation stimulated cell migration of cervical tumor cell lines . Tang and his colleagues identified that MARK1 overexpression was correlated with cell migration and proliferation in colorectal cancer via regulated miR-23a expression . KITLG, the gene encoding the ligand of the tyrosine-kinase receptor encoded by the KIT locus, which plays an essential role in the regulation of cell survival and proliferation, stem cell maintenance, mast cell development, migration. KITLG/SCF binding can active several signal transduction pathways [33–35]. KITLG mRNA expression levels were evaluated in testicular germ cell cancer, breast cancer, and gastrointestinal stromal tumors [36–39]. Overexpression of KITLG protein levels were correlated with increased tumor cell migration, proliferation, suggesting the tumorigenic role of KITLG [36, 38]. KITLG was significantly higher expressed in normal mammary gland epithelium tissue compared to breast tumor tissue, indicated that KITLG might be involved in the homeostasis of normal mammary and its disruption would confer to breast carcinogenesis . CRIP1 is a member of the LIM/double zinc finger protein family, which is highly expressed in intestine and immune cells . In gastric cancer, CRIP1 was over-expressed in primary tumor tissues, and confirmed as an independent prognostic factor. Patients with gastric carcinoma over-expression of CRIP1 had a shorter overall survival . Compared to adjacent normal tissues, CRIP1 was significantly higher expressed in cervical cancer, and it was significantly associated with FIGO stage .
The Connectivity map database was further used to screen out small-molecule drugs with promising capacity as therapeutic goals for NPC. To screen out potential small-molecule drugs to treat NPC, 66 candidate small-molecule drugs were obtained from the prediction of CMAP database based on the final hub genes of NPC. Among the top ten most significant potential small-molecule drugs, vorinostat and thalidomide were particularly interesting and have anti-tumor effects in NPC treatment. Vorinostat is a histone deacetylase inhibitors (HDACi), which has shown strong anti-tumor effects in various types of solid cancers, when combined with other traditional chemotherapeutic drugs like camptothecin and gemcitabine[44–49]. Thalidomide, is a glutamic acid derivative, which was a classic drug with immune-modulatory properties and tumor necrosis factor alpha inhibits [50–52]. Subsequent studies found that thalidomide has anti-angiogenic, anti-inflammatory, anti-fibrotic and immune-modulatory effects, and the clinical effectiveness of thalidomide has been confirmed in the treatment of certain disease such as refractory Crohn’s disease, lung metastasis, multiple myeloma, hepatocellular carcinoma, and breast carcinoma[53–60]. Our results based on the CMAP database may provide several potential small-molecule drugs as to future therapy for NPC; nevertheless, studies in vivo and in vitro experiments are necessary.
In summary, through the construction of weighted gene co-expression network with data from the GEO database, our study identified four hub genes correlated with prognostic in NPC tumor, which may contribute to the new insights for NPC therapy, and several potential small-molecule drugs for NPC treatment. Meanwhile, further studies, including in vivo and in vitro experiments, are necessary to elucidate potential molecular mechanism of hub genes for future clinical applications.