Lung cancer has one of the highest rates of incidence and mortality among all types of malignant tumors (Bray et al., 2018). Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers (El-Zein et al., 2017; Colling et al., 2019). Lung adenocarcinoma (LUAD), the most common type of NSCLC and accounting for approximately 40% of all lung cancers, is one of the leading causes of respiratory cancer-associated deaths (Maemura et al., 2018; Kleczko et al., 2019). With the use of highly sensitive low dose computerized tomography (CT) to detect lung cancer, and an increase in the overall awareness about the prevention and diagnosis of early NSCLC, the prognosis of NSCLC patients has significantly improved (Hasan et al., 2014; Kassem et al., 2019). Nevertheless, owing to the insidious nature of NSCLC progression, most of the patients still present at an advanced stage upon diagnosis. Consequently, most of these patients cannot be surgically treated and respond poorly to radiotherapy and chemotherapy, resulting in a <15% chance of 5-year survival (Molina et al., 2008; Li et al., 2018). The advent of targeted therapy holds promise among NSCLC patients, especially among LUAD patients; however, the poor prognosis still remains a concern. Therefore, it is important to identify new biomarkers for early stratification and diagnosis of high-risk lung cancer patients with a poor prognosis.

Six-transmembrane epithelial antigen of prostate-1 (STEAP1), also known as PRSS24, belonging to the STEAP family, is a cell surface antigen overexpressed in various tumors and is closely associated with the prognosis of numerous malignant tumors (Grunewald et al., 2012a; Ihlaseh-Catalano et al., 2013; Lee et al., 2016; Barroca-Ferreira et al., 2018). STEAP1 is upregulated in prostate cancer and associated with a high Gleason score, seminal vesicle invasion, and biochemical recurrence (BCR) (Ihlaseh-Catalano et al., 2013). Targeting STEAP1 expression may potentially inhibit the proliferation of and induced apoptosis in prostate cancer cells (Gomes et al., 2014, 2018). However, STEAP1 downregulation has been reported in endometrial carcinoma, and STEAP1 upregulation is associated with a better patient prognosis rather than STEAP1 downregulation (Sun et al., 2019). In contrast, some studies have indicated that STEAP1 upregulation is associated with reduced growth and migration of endometrial cancer cells (Sun et al., 2019). Furthermore, STEAP1 is reportedly upregulated in Ewing’s tumor and colorectal cancer, and the prognosis of patients with high STEAP1 expression levels was better than that of patients with low expression levels (Grunewald et al., 2012c; Lee et al., 2016; Nakamura et al., 2019). STEAP1 is aberrantly expressed in multiple tumors and is associated with the occurrence, development, and prognosis of malignant tumors, indicating that STEAP1 might be a potential diagnostic and therapeutic marker for cancers. In addition, Zhuang et al. (2015) first reported that STEAP1 is upregulated in lung cancer tissues. However, the role and potential value of STEAP1 in LUAD has not been reported. This study aimed to analyze the expression and clinical significance of STEAP1 in LUAD and to explore the role of STEAP1 in the occurrence and progression of LUAD and the potential mechanism underlying its regulatory functions.

Six-transmembrane epithelial antigen of prostate-1 is reportedly aberrantly regulated in numerous cancers, including prostate cancer, Ewing’s sarcoma, breast cancer and colorectal cancer, and is associated with the prognosis of cancer patients (Grunewald et al., 2012c; Ihlaseh-Catalano et al., 2013; Gomes et al., 2014; Lee et al., 2016; Barroca-Ferreira et al., 2018; Nakamura et al., 2019; Sun et al., 2019; Xie et al., 2019). Compared with tumor-adjacent normal tissues and benign prostatic hyperplasia (BPH) tissue, STEAP1 was upregulated in prostate cancer and prostatic intraepithelial neoplasia (PIN). Furthermore, STEAP1 expression levels are positively associated with the Gleason score and BCR (Ihlaseh-Catalano et al., 2013; Gomes et al., 2014). In contrast, STEAP1 was upregulated in the normal human endometrium and downregulated in most endometrial cancer tissue specimens. STEAP1 downregulation is associated with the degree of malignancy, tumor differentiation, and lymph node metastasis in endometrial cancer. Furthermore, the prognosis of patients with endometrial cancer with high STEAP1 expression levels was significantly better than that of patients with low STEAP1 expression levels (Sun et al., 2019). Moreover, STEAP1 was downregulated in breast cancer tissues and negatively correlated with the TNM stage, tumor grade, and lymph node metastasis in breast cancer patients. Kaplan–Meier analysis previously revealed that breast cancer patients with low STEAP1 expression levels tended to have a poor prognosis (Xie et al., 2019). Additionally, Zhuang et al. first reported that STEAP1 is upregulated in lung cancer tissue; however, no further assessment was conducted (Zhuang et al., 2015). This study shows that STEAP1 is upregulated in LUAD tissue, which is associated with the TNM stage and LNM. These results were further confirmed using the RNA-seq data from TCGA and GEO databases. Together, these results suggest that STEAP1 is a potential prognostic biomarker for LUAD.

The cell cycle is closely associated with the tumorigenesis and cancer progression. For instance, Wang et al. reported that the p53/p21 signaling pathway potentially inhibits SPAG5 expression, thereby regulating the proliferation and migration of LUAD cells (Wang T. et al., 2019). Similarly, Tan et al. reported that TNKS1BP1 was upregulated in LUAD and promoted cell cycle transformation (S phase accumulation and M phase decrease), and was associated with a poor prognosis of cancer patients. Furthermore, they reported that TNKS1BP1 regulates genome stability by influencing homologous recombination (Tan et al., 2017). Through Metascape analysis, this study shows that STEAP1 is involved in processes closely associated with tumorigeneses, such as cell division, cytokine production, cytokine signaling, and DNA replication. Further, KEGG analysis indicated that genes co-expressed with STEAP1 were involved in the cell cycle, the IL-17 signaling pathway, ECM receptor interaction, apoptosis, the NF-kB signaling pathway, and the TNF signaling pathway. These results were further validated via GSEA, which revealed that STEAP1 upregulation was associated with homologous recombination, the p53 signaling pathway, cell cycle, DNA replication, apoptosis, and the Toll-like receptor signaling pathway. STEAP1 silencing reportedly inhibited the activity and proliferation of LNCaP cells and induced apoptosis in prostate cancer by affecting p53, p21, Bax, Bax/Bcl-2, Caspase-9, FasL, Caspase-8, and Caspase-3 (Gomes et al., 2018). Furthermore, STEAP1 silencing inhibited proliferation, clonal formation, and invasion in vitro and in vivo in Ewing’s tumor. Moreover, STAT1 activation would be inhibited upon STEAP1 knockout (Grunewald et al., 2012b). Interference of STEAP1 inhibited proliferation but promoted apoptosis and increased the production of reactive oxygen species (ROS) in colorectal cancer cells. Considering the potential underlying mechanism, STEAP1 silencing inhibited the expression of nuclear erythroid 2-related factor (NRF2) in colorectal cancer cells (Nakamura et al., 2019) but promoted cell cycle transformation (G-S phase), thereby promoting cell proliferation and enhancing cell invasion, migration, and tumorigenesis in nude mice. Furthermore, STEAP1 knockdown inhibited the expression of E-cadherin but promoted the expression of N-cadherin, Vimentin, Snail, Slug, Twist, MMP2, and MMP9 (Sun et al., 2019). Therefore, based previous and the present data, we believe that STEAP1 potentially promotes the occurrence and progression of LUAD through its effects on the cell cycle, DNA replication, and apoptosis.

The 10 hub genes identified herein in the PPI network were closely associated with the cell cycle and potentially play a pivotal role in LUAD pathogenesis. CDK1 upregulation has been reported in LUAD and is reportedly associated with a poor patient prognosis (Liu W. T. et al., 2018). Further, nadroparin potentially inhibits the growth of LUAD-derived A549 and CALU1 cells by downregulating CDK1 (Carmazzi et al., 2012). In a related study, inhibition of UBE2C, an upregulated marker of esophageal squamous cell carcinoma, inhibited the growth of esophageal squamous cell carcinoma by modulating the expression of CCNB1, which was one of the ten hub genes identified in our previous study (Palumbo et al., 2016). CCNA2 is reportedly upregulated in NSCLC tissues and associated with a poor patient prognosis (Ko et al., 2013). Furthermore, CCNB2, MAD2L1, BUB1, and NCAPG are significantly upregulated in hepatocellular carcinoma (HCC) tissues and are implicated in the growth and metastasis of HCC cells (Li et al., 2017, 2019; Xu et al., 2017; Liu K. et al., 2018). BIRC5 is reportedly upregulated in ovarian cancer cells, and its inhibition impeded the growth and migration of ovarian cancer cells (Wang et al., 2018). KIF4A, another hub gene identified herein, is reportedly upregulated in colorectal cancer tissues and cell lines and was significantly associated with patient clinicopathological features including OS and DFS herein. Interestingly, KIF4A exerted its tumorigenic effects by regulating the cell cycle and cell proliferation (Hou et al., 2018). Together, these results show that the hub genes identified herein play a role in the occurrence and progression of numerous tumors by regulating various signaling pathways. These results also support our hypothesis that upregulation of CDK1, UBE2C, CCNA2, CCNB1, CCNB2, MAD2L1, BIRC5, BUB1, NCAPG, and KIF4A is potentially associated with a poor prognosis of LUAD patients. However, we could not unravel the complex interactions among these hub genes and STEAP1, and our results warrant further experimental verification to confirm their interplay in LUAD.

The present results show that STEAP1 is upregulated in LUAD and is associated with the clinicopathological features and prognosis of LUAD patients. Moreover, STEAP1 potentially promotes the occurrence and progression of LUAD by regulating homologous recombination, the p53 signaling pathway, cell cycle, DNA replication, and apoptosis, thus serving as a potential prognostic biomarker for LUAD.

Publicly available datasets were analyzed in this study. The datasets generated for this study can be accessed in The Cancer Genome Atlas (TCGA) database [https://portal.gdc.cancer.gov/projects/TCGA-LUAD(HTSeq-FPKM)] and NCBI Gene Expression Omnibus (GEO), GSE2514 (GPL8300), and GSE10072 (GPL96) (http://www.ncbi.nlm.nih.gov/geo).

The study involving human participants was reviewed and approved by the Ethics Committee of the Affiliated Hospital of Zunyi Medical University. The patients/participants provided written informed consent to participate in this study.

All authors contributed toward completing this study, read, and approved the final manuscript. GX, QG, and H-LL conceived the research topic, made the research plan, and directed the implementation of the experiments. QG and XK contributed equally to analyze the data and draft the manuscript. ZL, W-LG, and S-XF assisted in data analysis and drafting the manuscript. CC, Y-XS, and HH involved in the management of lung cancer samples and the collection of related data.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MC and handling Editor declared their shared affiliation at the time of review.