CPSF3 is a promising prognostic biomarker and predicts recurrence of non‑small cell lung cancer
- Authors:
- Published online on: July 24, 2019 https://doi.org/10.3892/ol.2019.10659
- Pages: 2835-2844
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Copyright: © Ning et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Lung cancer is a type of malignant tumor that causes considerable mortality and morbidity worldwide (1). Out of all lung cancer cases, >85% are non-small cell lung cancer (NSCLC) (2). Surgical intervention, chemotherapy and radiation therapy are the traditional therapies for early-stage lung cancer; however, all these treatments are accompanied by undesirable adverse reactions. In recent years, molecular targeted therapies, which specifically target carcinoma cells, and reportedly have minimal adverse effects compared with conventional treatments, have become a research focus (3). Currently, a large amount of molecular therapies targeting diverse receptor tyrosine kinases (RTKs), which have been demonstrated to be frequently mutated and to promote tumorigenesis by regulating cell proliferation and survival, are widely used in patients with NSCLC (4). Numerous types of RTKs, including epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-Met), ALK receptor tyrosine kinase (ALK) and BRAF, which have been reported to be frequently mutated in patients with NSCLC, have been used as targets in clinical therapy (5–10). However, despite all these therapies, the majority of patients with NSCLC still exhibit a poor 5-year survival rate of 15.9% (11). Therefore, there is an urgent need to identify biomarkers with better prognostic and diagnostic potential.
The cleavage polyadenylation specificity factor (CPSF) complex is a core component of 3′-end processing and is involved in regulating mRNA maturation and alternative splicing, as well as internal introns, by modulating the cleavage and polyadenylation of mRNAs (12). The multi-subunit CPSF complex is composed of CPSF1 (also known as CPSF160), CPSF2 (also known as CPSF100), CPSF3 (the cleavage endonuclease, also known as CPSF73), CPSF4 (also known as CPSF30), factor interacting with poly(A) polymerase α and CPSF1 (FIP1L1; also known as FIP1) and WD repeat domain 33 (12). There are several studies regarding the function of the CPSF complex in cancer, particularly in lung cancer; however, CPSF1 promotes cell proliferation in human ovarian cancer (13). Decreased CPSF2 expression promotes invasion and an increased cancer stem cell population, and CPSF2 may be a novel prognostic marker for papillary thyroid carcinoma (14,15). Suppression of CPSF4 inhibits the proliferation of lung adenocarcinoma (LUAD) cells and is associated with overall survival (OS) (16–19). FIP1L1 is generated via gene fusion with platelet-derived growth factor receptor a, which is recognized as an important diagnostic marker of hematological malignancies, including chronic eosinophilic leukemia, hypereosinophilic syndrome and systemic mastocytosis, and occasionally atypical chronic myelogenous leukemia (20). Therefore, it was hypothesized that potential diagnostic and prognostic biomarkers could exist within the CPSF complex.
The Cancer Genome Atlas (TCGA; http://portal.gdc.cancer.gov) is an open-access database that is widely used globally and provides a reliable tool for the analysis of numerous types of useful clinicopathological data. In addition, TCGA data is overseen by the National Cancer Institute's Center for Cancer Genomics (21). Genetic and clinicopathological data of >1,000 patients with primary LUAD and lung squamous cell carcinoma (LUSC) are recorded in the TCGA Lung Cancer Cohort (22).
In the present study, promising biomarkers for NSCLC were identified via bioinformatics data mining. The results of the present study demonstrated that CPSF3 of the CPSF complex was overexpressed in NSCLC, and its overexpression was associated with OS and recurrence-free survival (RFS) of patients with LUAD. CPSF3 may also serve as a diagnostic biomarker for LUAD and LUSC. Additionally, CPSF3 may promote the proliferation and lymph node metastasis of LUAD. The mechanism of CPSF3 overexpression may be connected to its DNA copy number variants and DNA hypermethylation.
Materials and methods
TCGA Lung Cancer Cohort
TCGA Lung Cancer Cohort data, (http://tcga.cancer.gov/dataportal; accessed June 2016), which include the LUAD cohort, comprising 706 primary LUAD tissues and normal lung tissues, and the LUSC cohort, comprising 554 primary LUSC tissues and normal lung tissues, were downloaded from the University of California Santa Cruz Xena Browser (https://xenabrowser.net). Excel 2016 (Microsoft Corporation) was used for further data processing. From the cohorts, 520 primary LUAD cases and 506 primary LUSC cases with existing RNA-seq and intact clinical parameters were selected for further analysis. In addition, DNA methylation data (‘Illumina 450k methylation’) and CNA data (‘gene-level GISTIC2-processed’) were downloaded from this database to detect the possible mechanisms of abnormal expression of CPSF3 in LUAD.
Cancer cell line encyclopedia (CCLE)
CCLE (https://portals.broadinstitute.org/ccle/about) is a database containing genomic data, including copy number, mRNA expression, reverse-phase protein microarray and reduced representation bisulfite sequencing, from >1,100 cell lines. LUAD cell line data (based on The Global Bioresource Center; http://www.atcc.org) were downloaded to examine the association between CPSF3 expression and its DNA methylation.
Statistical analysis
GraphPad Prism version 5.0 (GraphPad Software, Inc.) or SPSS version 16.0 (SPSS, Inc.) were used for data analysis. Unless specifically mentioned, all values are presented as the mean ± SD. Two-group independent sample comparisons were performed using a Student's t-test (two-tailed) when the two groups had equal variances, while Welch's t-test was used for unequal variances. Multi-group samples statistics were analyzed via one-way ANOVA if the variances were equal; if not, Welch's ANOVA was performed. Bonferroni post hoc tests were performed for all ANOVAs. Samples from TCGA Lung Cancer Cohort were divided into two groups, according to median values. OS and RFS curves were plotted using the Kaplan-Meier method, and OS and RFS differences were assessed using the log-rank test. Receiver operating characteristic (ROC) curves were constructed using CPSF3 expression data, and the area under the curve (AUC) was estimated to investigate the feasibility of distinguishing LUAD from LUSC. Pearson correlation analysis was used to evaluate the correlations among CPSF3 mRNA expression and CPSF3 DNA methylation and DNA copy number variants (CNAs). P<0.05 was considered to indicate a statistically significant difference.
Results
CPSF complex is significantly elevated in NSCLC tissues compared with normal lung tissues (NTL)
Expression levels of CPSF complex components were individually assessed in the TCGA LUAD and LUSC cohorts. The results indicated that all CPSF complex components were significantly overexpressed in LUAD (Fig. 1) and LUSC (Fig. 2) tissues compared with NTL.
CPSF3 is the only component associated with lung cancer OS and RFS in the CPSF complex
To identify potential prognostic biomarkers in the CPSF complex, the associations among the CPSF complex components and OS and RFS in the TCGA Lung Cancer Cohort were assessed. The results of the present study demonstrated that overexpression of CPSF3 and FIP1L1 in patients with LUAD was associated with decreased survival times compared with patients with low expression levels of CPSF3 and FIP1L1 (Fig. 3). In patients with LUSC, no CPSF complex components were significantly associated with OS (Fig. 4). Additionally, analysis of the association between the CPSF complex component proteins and RFS was investigated. Patients with LUAD with high CPSF2 and CPSF3 had shorter RFS than those in the low expression groups (Fig. 5), whereas expression of the components had no effect on RFS of patients with LUSC (Fig. 6). Taken together, CPSF3 was the only CSPF complex component that affected OS and RFS, and it may thus function as a promising prognostic biomarker for NSCLC. Therefore, CPSF3 was considered as a potential biomarker and focused on in further research.
CPSF3 serves as a biomarker to distinguish between histological subtypes of NSCLC
To further test whether CPSF3 could serve as a biomarker to distinguish between LUAD and LUSC, CPSF3 expression status of patients with LUAD and LUSC in the TCGA Lung Cancer Cohort was compared. As shown in Fig. 7A, the average expression level of CPSF3 among 502 patients with LUSC was higher than that of 512 patients with LUAD. ROC analysis further demonstrated that CPSF3 expression could be a single significant parameter to discriminate between LUAD and LUSC, with an AUC of 0.7014 (Fig. 7B). To further explore the clinical implications of CPSF3, associations among CPSF3 expression and different molecular subtypes were investigated within different types of adenocarcinoma classified according to the genotypes of BRAF, erb-b2 receptor tyrosine kinase 4 (ERBB4), EGFR, echinoderm microtubule associated protein like 4, KRAS and serine/threonine kinase 11, and ALK translocation, in the TCGA-LUAD cohort. There was no difference in CPSF3 between the wild type and mutant samples categorized by any of the aforementioned genes of interest (Fig. 7C-H). Overall, CPSF3 was shown to be a novel and efficient diagnostic biomarker for distinguishing between LUAD and LUSC in NSCLC.
Association of CPSF3 expression with clinicopathological features in LUAD
To explore the role of high CPSF3 expression in LUAD progression, the association of clinicopathological features with CPSF3 expression was evaluated. The present study revealed that CPSF3 expression was associated with smoking history, tumor diameter, lymph node metastasis, TNM stage and radiation therapy, whereas there was no association with age, gender, distant metastasis and targeted molecular therapy in the TCGA-LUAD Cohort (Table I). Therefore, it was hypothesized that CPSF3 may promote proliferation and metastasis, and may be associated with radiation therapy.
 | Table I.Association of CPSF3 with clinicopathological features in The Cancer Genome Atlas lung adenocarcinoma patients. |
DNA methylation and DNA CNAs are correlated with CPSF3 expression in LUAD
DNA methylation is one of the most common factors associated with abnormal gene expression. By analyzing CPSF3 DNA methylation and RNA-seq data in the TCGA-LUAD Cohort, two CPSF3 DNA methylation CpG sites (cg12057242 and cg25739938) were identified to be differentially methylated in TCGA-LUAD tissues compared with normal lung tissues (Table II). The correlation between the two differentially expressed DNA CpG sites and RNA expression was assessed, demonstrating that cg25739938 exhibited a negative correlation with CPSF3 expression (Fig. 8A and B). However, the same analysis conducted in 53 LUAD cell lines from CCLE indicated there was no correlation between CPSF3 expression and methylation (Fig. 8C). DNA CNAs are another mechanism that leads to aberrant RNA expression. Therefore, the association between CPSF3 DNA CNAs and RNA expression was further analyzed. The results demonstrated that CPSF3 CNAs were positively correlated with CPSF3 mRNA expression in TCGA-LUAD samples (Fig. 8D) and CCLE-LUAD cell lines (Fig. 8E).
Discussion
Previously, a number of promising potential biomarkers have been identified in a series of secondary analyses using TCGA data. For example, DNA methylation of SOX30 is correlated with myelodysplastic syndrome progression, and has been reported to act as a potential predictive and prognostic biomarker in acute myeloid leukemia (23). Higher FOS expression is associated with a better outcome in breast cancer datasets (24). Using public data from TCGA, a 22-gene signature that demonstrated the best predictive value for assessing the clinical benefit of postoperative chemoradiotherapy was established (25).
Compound gene analysis is a more effective way of elucidating novel biomarkers and assessing the interactions among individual genes. Targeting one of these genes may lead to a large feedback effect. CPSF complex components have been demonstrated to regulate the cleavage and polyadenylation of mRNAs during the mRNA maturation and alternative splicing processes (12). However, there are few reports regarding the role of CPSF4 in lung cancer (16–19), and, to the best of our knowledge, no reports on the other components. Therefore, TCGA data was utilized to elucidate potential prognostic and diagnostic biomarkers within the complex in the present study.
In the present study, CPSF complex components were first evaluated in terms of their expression levels in NSCLC using TCGA data, as biomarkers must be differentially expressed between cancer tissue and normal tissue. The results of the present study indicated that expression of all CPSF complex components was increased in NSCLC. A promising biomarker should affect prognosis and recurrence, and may therefore serve as a predictor. The associations of CPSF complex expression with OS and RFS were assessed, which demonstrated that CPSF3 was the only component that affected OS and RFS in LUAD. Additionally, there is only one previous report regarding the role of CPSF3 in cancer (26), and, to the best of our knowledge, no reports regarding the role of CPSF3 in lung cancer; therefore, the present study focused on CPSF3 for further research, as it appeared to be a potentially promising biomarker. Further ROC curve analysis demonstrated that CPSF3 may serve as a diagnostic biomarker for NSCLC to distinguish between LUAD and LUSC.
A previous study in prostate cancer demonstrated that knockdown of CPSF3 by a specific siRNA induces apoptosis (26), which verified that CPSF3 is associated with the proliferation of malignant carcinoma. To further assess the role of CPSF3 in LUAD, the association between clinicopathological features and CPSF3 was assessed. The present study revealed that CPSF3 expression was associated with smoking history, tumor diameter, lymph node metastasis, TNM stage and radiation therapy; thus, CPSF3 may affect LUAD proliferation and metastasis, consistent with the results of the aforementioned study in prostate cancer (26).
The mechanism of gene dysregulation in NSCLC is complex. Among all the mechanisms, genetic and epigenetic alterations, including DNA amplification, DNA methylation and somatic mutations, commonly lead to abnormal gene expression accompanied by anomalous cancer cell behavior. For instance, heteroclite sulfatase 2 methylation acts as a prognostic marker for lung cancer survival (27). ERBB2 amplification results in erlotinib resistance in EGFR-L858R mutated tyrosine kinase inhibitor-naïve LUAD (28). c-Met overexpression, HER-2 gene amplification and spectrin β non-erythrocytic 1-ALK gene fusion have been reported to coexist in LUAD, and this may become a novel biomarker for cancer that is refractory to crizotinib, chemotherapy and radiotherapy, and poor prognosis (29). Promoter methylation of cadherin 13 is strongly associated with LUAD and may function as a promising diagnostic biomarker for LUAD (30). Thus, the present study assessed whether DNA CNA and abnormal DNA methylation were the mechanism underlying the aberrant mRNA expression of CPSF3, similar to the aforementioned gene. In the present study, DNA methylation levels in TCGA LUAD tissues were compared with levels in normal lung tissues, which revealed two differentially expressed CpG sites. Further correlation analysis confirmed that cg25739938 was negatively correlated with CPSF3 expression, while cg12057242 in TCGA-LUAD Cohort patients and in LUAD cell lines has no correlation with CPSF3 expression. The aforementioned results suggested that the hypermethylation of cg25739938 may be the potential mechanism affecting CPSF3 mRNA expression in LUAD. Furthermore, the DNA amplification status of CPSF3 was detected. The results demonstrated that DNA CNAs were closely associated with increased CPSF3 expression, in TCGA LUAD Cohort patients and 53 LUAD cell lines. Overall, the dysregulation of CPSF3 may be caused by DNA methylation and DNA CNAs.
In summary, the present study is the first to elucidate the potential role of the CPSF complex, particularly CPSF3, in proliferation and migration in lung cancer. As the present study was conducted via bioinformatics analysis, experimental studies regarding the role of CPSF3 in LUAD will be performed in order to verify the results of the present study. In conclusion, aberrant CPSF3 expression may be regulated by DNA CNAs, and it may function as a promising prognostic and diagnostic biomarker for LUAD.
Acknowledgements
Not applicable.
Funding
This study was funded by the National Nature Science Foundation of China (grant no. 81401391) and the National Nature Science Foundation of Guangdong Province (grant no. 2015A030313452).
Availability of data and materials
The datasets used during the present study are available from the corresponding author upon reasonable request. Data were obtained from The Cancer Genome Atlas (TCGA; http://portal.gdc.cancer.gov), CCLE (https://portals.broadinstitute.org/ccle/about); The Global Bioresource Center (http://www.atcc.org) and the University of California Santa Cruz Xena Browser (https://xenabrowser.net).
Authors' contributions
YN conceived and designed the study. WL performed the bioinformatics analysis. XG helped design the project and wrote the paper. XX analyzed the data, reviewed and checked the manuscript. YZ proposed the concept of the study, analyzed and interpreted the data, supervised the research throughout, managed the project and funding and revised the article for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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