Received: 5 February 2019 | Revised: 30 April 2019 | Accepted: 1 May 2019

DOI: 10.1002/jcp.28839

ORIGINAL RESEARCH ARTICLE

Identification and validation of key genes associated with

non‐small‐cell lung cancer

Qiang Ma1,2,3* | Yuan Xu1,2,3* | Hebin Liao2 | Yan Cai1,2,3 | Lei Xu2 | Dan Xiao1,2,3 |
Chang Liu 1,2,3
| Wenjie Pu1,2,3 | Xiaowu Zhong 1,2,3
| Xiaolan Guo 1,2,3

1
Department of Clinical Laboratory, Affiliated
Hospital of North Sichuan Medical College,
Nanchong, China
2
Translational Medicine Research Center,
North Sichuan Medical College, Nanchong,
China
3
Department of Laboratory Medicine, North
Sichuan Medical College, Nanchong, Sichuan,
China
Correspondence
Xiaowu Zhong and Xiaolan Guo, Department
of Clinical Laboratory, Affiliated Hospital of
North Sichuan Medical College, 63 Wenhua
Road, Nanchong, 637000 Sichuan, P.R. China.
Email: zxw_strive@163.com (X.Z.); alan5200@
hotmail.com (X.G.)
Funding information
Scientific Research Fund of Sichuan Provincial
Health and Family Planning Commission,
Grant/Award Numbers: 17PJ588, 16PJ131;
Science and Technology Support Program of
Nanchong, Grant/Award Numbers:
NCKL201703, 18SXHZ0579, 16YFZJ0133
Abstract
Non‐small‐cell lung cancer (NSCLC) is one of the main causes of death induced by
cancer globally. However, the molecular aberrations in NSCLC patients remain
unclearly. In the present study, four messenger RNA microarray datasets
(GSE18842, GSE40275, GSE43458, and GSE102287) were downloaded from the
Gene Expression Omnibus (GEO) database. Differentially expressed
genes (DEGs) between NSCLC tissues and adjacent lung tissues were obtained
from GEO2R and the overlapping DEGs were identified. Moreover, functional
and pathway enrichment were performed by Funrich, while the protein–protein
interaction (PPI) network construction were obtained from STRING and hub
genes were visualized and identified by Cytoscape software. Furthermore,
validation, overall survival (OS) and tumor staging analysis of selected hub genes
were performed by GEPIA. A total of 367 DEGs (95 upregulated and 272
downregulated) were obtained through gene integration analysis. The PPI
network consisted of 94 nodes and 1036 edges in the upregulated DEGs and 272
nodes and 464 edges in the downregulated DEGs, respectively. The PPI network
identified 46 upregulated and 27 downregulated hub genes among the DEGs, and
six (such as CENPE, NCAPH, MYH11, LRRK2, HSD17B6, and A2M) of that have not
been identified to be associated with NSCLC so far. Moreover, the expression
differences of the mentioned hub genes were consistent with that in lung
adenocarcinoma and lung squamous cell carcinoma in the TCGA database.
Further analysis showed that all the six hub genes were associated with tumor
staging except MYH11, while only the upregulated DEG CENPE was associated
with the worse OS of patients with NSCLC. In conclusion, the current study
showed that CENPE, NCAPH, MYH11, LRRK2, HSD17B6, and A2M might be the
key genes contributed to tumorigenesis or tumor progression in NSCLC, further
functional study is needed to explore the involved mechanisms.

KEYWORDS
key genes, microarray, non‐small‐cell lung cancer

*Qiang Ma and Yuan Xu contributed equally to this work.

J Cell Physiol. 2019;1–11. wileyonlinelibrary.com/journal/jcp © 2019 Wiley Periodicals, Inc. | 1

2 |
1 | INTRODUCTION
Lung cancer is the primary cause of malignant tumor‐related
mortality worldwide, the morbidity of lung cancer is still
increasing in China (She, Yang, Hong, & Bai, 2013). Non‐small‐
cell lung cancer (NSCLC), the most common type of lung cancer, is
considered as a complicated disease. The causes of NSCLC
consist of gene aberrations and environmental influence. Com-
pared with histological classification, genes play more and more
important role in the diagnosis, treatment, and prognosis of
NSCLC. For instance, genotype‐based treatment of the epidermal
growth factor receptor (EGFR) gene for lung cancer is helpful for
slowdown disease progression and decrease NSCLC associated
mortality (Mitsudomi & Yatabe, 2007). To date, the precise
molecular mechanisms of NSCLC are still unknown, it is
extremely important to uncover the underlying genes contrib-
uted to NSCLC.
With the rapid development of microarray technology, some
high throughput platforms for analysis of gene expression are
widely used to explore the differentially expressed genes (DEGs)
during tumorigenesis and molecular mechanisms of anticancer
drugs (Konstantinopoulos et al., 2008; Lu et al., 2010; Sun et al.,
2012). Many gene expression profiling studies on NSCLC have
been performed using microarray technology and identified many
DEGs associated with NSCLC (Mitchell, Zingone, Toulabi, Boeck-
elman, & Ryan, 2017; Wei et al., 2014). However, the DEGs
identified with microarray dependent on the sample size, tumor
staging, grading, and ethnic group, etc. The overlapping genes
obtained from different microarrays might be more representa-
tive.
In the present study, four messenger RNA (mRNA) microarray
datasets (GSE18842, GSE40275, GSE43458, and GSE102287)
were downloaded from Gene Expression Omnibus (GEO) data-
base, which were subsequently analyzed to obtain overlapping
DEGs. Functional enrichment and network construction were
applied to identify the key genes associated with NSCLC.
2 | MATERIALS AND METHODS
2.1 | Data acquisition
First, “Non small cell lung cancer” or “Lung squamous cell
carcinoma” or “Lung adenocarcinoma” or “Large cell lung cancer”
were searched in GEO (www.ncbi.nlm.nih.gov/geo) database, then
followed by the including criteria of selected datasets: (a) The
used tissue samples should be obtained from human NSCLC and
the corresponding adjacent or normal tissues, (b) the microarray
or RNA‐sequencing data should include mRNA, (c) at least 15 pair
of samples were included. Finally, four microarray expression
profile datasets GSE18842, GSE40275, GSE43458, and
GSE102287 were downloaded from the GEO database, which
were based on GPL570 Affymetrix Human Genome U133 Plus 2.0
MA ET AL.
Array or Human Exon 1.0 ST Array platform, The GSE18842 was
submitted by Sanchez‐Palencia et al. (2011), including 32
squamous cell carcinoma, 14 adenocarcinoma, and 45 adjacent
lung tissues. The GSE40275 was submitted by Kastner and
colleagues including 16 NSCLC and 43 adjacent lung tissues.
The GSE43458 was submitted by Kabbout et al. (2013), including
80 lung adenocarcinoma and 30 normal lung tissues. The
GSE102287 was submitted by Mitchell et al. (2017) including 32
NSCLC and 34 adjacent lung tissues.
2.2 | Data preprocessing and identification of DEGs
In this study, GEO2R (http://www.ncbi.nlm.nih.gov/geo/geo2r/)
was applied to uncover DEGs between non‐small‐cell lung cancer
tissues and adjacent lung tissues. GEO2R is an interactive web
tool that compares two groups of samples under the same
experimental conditions and can analyze most of the GEO series
(Barrett et al., 2013). The adjusted p values (adj. p) were used to
correct the occurrence of false‐positive results using Benjamini
and Hochberg false discovery rate method by default. DEGs were
selected out using GEO2R according to the criteria that adj. p
smaller than .05 and absolute log fold‐change greater than 1.
2.3 | Functional annotation, pathway enrichment,
protein–protein interaction network construction of
DEGs
Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes
(KEGG) pathway enrichment analysis, and the interactions among the
DEGs were explored with the Search Tool for the Retrieval of
Interacting Genes/Proteins database (STRING; https://string‐db.org/;
Szklarczyk et al., 2015). The functional enrichment analysis including
biological process, molecular function, and cellular component terms
was performed to classify DEGs by FunRich, which is a stand‐alone
software used mainly for functional enrichment and interaction
network analysis of genes and proteins (Pathan & Keerthikumar,
2017). Based on the STRING database, the protein–protein interac-
tion (PPI) networks were constructed by Cytoscape software
(Shannon et al., 2003). Degree more than 10 was set as a cut‐off
criterion and identified as hub genes.
2.4 | Hub genes validation by GEPIA
After hub genes identified from these four microarray expression
profile datasets, Gene Expression Profiling interactive analysis
(GEPIA; http://gepia.cancer‐pku.cn/; Tang et al., 2017) was used
to validate the selected upregulated and downregulated hub
genes. GEPIA is an online tool for gene expression analysis
between tumor and normal data from The Cancer Genome Atlas
(TCGA) and the Genotype‐Tissue Expression (GTEx). It provides
data such as gene expression, tumor staging, and survival period
MA ET AL. | 3

for 33 kinds of cancers including lung adenocarcinoma and lung 3 | RESULTS

squamous cell carcinoma.
2.5 | Tumor staging and overall survival analysis
using the selected hub genes
After literature review, we found that two upregulated hub genes (CENPE
and NCAPH) and four downregulated hub genes (MYH11, LRRK2,
HSD17B6, and A2M) have not been identified associated with NSCLC.
GEPIA was used to analyze the contributions of these hub genes to
tumor staging and overall survival (OS) period in NSCLC, and the staging
and survival curves were plotted.
3.1 | Identification of DEGs
A total of 1,415 upregulated and 1,784 downregulated DEGs were
identified from GSE18842 dataset, 2,713 upregulated DEGs and 2,200
downregulated DEGs were identified from GSE40275 dataset, 247
upregulated DEGs and 648 downregulated DEGs were identified from
GSE43458 dataset, and 1,381 upregulated DEGs and 1,941 down-
regulated DEGs were identified from GSE102287 dataset. The volcano
plot of each gene expression profile data was shown in Figure 1. Ninety‐
five upregulated and 272 downregulated overlapping DEGs were found
in NSCLC tissues compared with adjacent lung tissues (Figure 2).

F I G U R E 1 Volcano plots of gene expression profile data in NSCLC tissues and adjacent ones. (a) Volcano plot of GSE18842. (b) Volcano plot
of GSE40275. (c) Volcano plot of GSE43458. (d) Volcano plot of GSE102287. NSCLC: non‐small‐cell lung cancer [Color figure can be viewed at
wileyonlinelibrary.com]
4 | MA ET AL.

F I G U R E 2 Venn's diagrams and heat map of overlapping DEGs. (a) Venn's diagram of upregulated DEGs. (b) Venn's diagram of
downregulated DEGs. (c) Heat map of the upregulated (red) and downregulated (Blue) DEGs. DEG: differentially expressed gene
[Color figure can be viewed at wileyonlinelibrary.com]

3.2 | Enrichment analyses nodes were identified as hub genes. The PPI network of down-
regulated DEGs consisted of 272 nodes and 464 edges (data not
Enrichment analyses for the upregulated and downregulated DEGs
shown), and 27 nodes were identified as hub genes. Among these hub
were performed by FunRich. The upregulated DEGs were mainly
genes, the association of the two upregulated (CENPE and NCAPH)
enriched in “Spindle assembly” by biological process, “Microtubule” and
and four downregulated (MYH11, LRRK2, HSD17B6, and A2M) genes
“Kinetochore” by cellular component and “metalloendopeptidase
with NSCLC are needed to clarify. The expression of these hub genes
activity” by molecular function, respectively (data not shown). More-
between adjacent tissues and NSCLC tissues in the four microarray
over, KEGG pathways were enriched and the top two pathways were
datasets were shown in Figure 4. Thereafter we selected these hub
“Cell cycle and mitotic” and “PLK1 signaling events” (Figure 3). Similarly,
genes for further study.
the downregulated DEGs were mainly enriched in “Cell communication”
and “Signal transduction” by biological process, “plasma membrane” and
“Extracellular” by cellular component and “Cell adhesion molecule
3.4 | Hub genes validation
activity” by molecular function, respectively (data not shown). KEGG
pathways were enriched and the top two pathways were “Epithelial‐to‐ GEPIA, the online tool with data sourced from TCGA and GTEx,
mesenchymal transition” and “Hemostasis” (Figure 3). was used to validate the expression of these hub genes in NSCLC.
As shown in Figure 5, the expression of the upregulated hub genes
CENPE and NCAPH in lung squamous cell carcinoma were
3.3 | PPI network construction
significantly elevated compared with adjacent lung tissues. More-
The PPI network of upregulated DEGs consisted of 94 nodes and over, the expression of NCAPH in lung adenocarcinoma increased
1,036 edges (data not shown). As the criterion described above, 46 obviously, while the difference of CENPE between the two groups
MA ET AL.
F I G U R E 3 (a) Biological pathways for upregulated DEGs. (b) Biological pathways for downregulated DEGs. DEG: differentially expressed
gene [Color figure can be viewed at wileyonlinelibrary.com]
was not significant. Furthermore, the expressions of downregu-
lated hub genes MYH11, LRRK2, HSD17B6, and A2M were all in
consistent with that in GEPIA. These results revealed that the
selected hub genes were differentially expressed in NSCLC
universally.
3.5 | Clinic stage analyses
The expression of each hub gene in NSCLC patients was analyzed
according to the TNM stage. As shown in Figure 6, the expression
of CENPE and NCAPH was higher in patients with clinic Stage Ⅱ,
Stage Ⅲ or Stage Ⅳ than that in Stage Ⅰ, which revealed that these
upregulated hub genes might be associated with tumor progres-
sion positively. Similarly, the expression of LRRK2, HSD17B6, and
| 5
A2M were lower in patients with clinic Stage Ⅱ, Stage Ⅲ or Stage
Ⅳ than that in Stage Ⅰ, which demonstrated that these down-
regulated hub genes might be also predictors for NSCLC
progression.
3.6 | Overall survival analyses
To further elucidate whether these hub genes contributed to the
survival period in patients with NSCLC, we analyzed the OS for
each hub gene by GEPIA (Figure 7). The results showed that the
high expression of CENPE mRNA level was associated with the
worse OS in patients with NSCLC, while the OS differences
between high expression and low expression of the other five
genes were not significant, which revealed that CENPE was
6 | MA ET AL.

F I G U R E 4 The expression of six hub genes between NSCLC tissues and adjacent tissues from the selected microarray datasets. NSCLC: non‐
small‐cell lung cancer [Color figure can be viewed at wileyonlinelibrary.com]
MA ET AL. | 7

F I G U R E 5 Validation of selected hub genes in lung adenocarcinoma (LUAD) and lung square cell carcinoma (LUSC) from TCGA database.
(a) CENPE (b) NCAPH (c) A2M (d) HSD17B6 (e) LRRK2 (f) MYH11. TCGA: The Cancer Genome Atlas [Color figure can be viewed at
wileyonlinelibrary.com]

F I G U R E 6 Violin plots of selected hub genes in lung adenocarcinoma (LUAD) and lung square cell carcinoma (LUSC) from TCGA database.
(a) CENPE (b) NCAPH (c) A2M (d) HSD17B6 (e) LRRK2 (f) MYH11. TCGA: The Cancer Genome Atlas
8 |
F I G U R E 7 Overall survival curves of selected hub genes in lung adenocarcinoma (LUAD) and lung square cell carcinoma (LUSC) from TCGA
database. (a) CENPE (b) NCAPH (c) A2M (d) HSD17B6 (e) LRRK2 (f) MYH11. TCGA: The Cancer Genome Atlas [Color figure can be viewed at
wileyonlinelibrary.com]
associated with NSCLC tumor progression and might be used as a
tumor progression predictor for NSCLC patients.
4 | D IS C U S S IO N
Despite multimodal therapy has become norm therapeutic strategy,
the overall mortality of NSCLC has remained largely unchanged over
the past decades. The main cause is the lack of effective tools for
molecular alteration screening. Recently, microarray technology has
been widely used to identify molecular targets for diagnosis, therapy,
and prognosis for tumors. In the present study, 95 upregulated and
272 downregulated overlap DEGs were identified in NSCLC tissues
compared to adjacent lung tissues from microarray datasets
GSE18842, GSE40275, GSE43458, and GSE102287. These upregu-
lated genes were mainly enriched in “spindle assembly” and
“metallopeptidase activity”, which were closely related to tumorigen-
esis or metastasis. The downregulated genes were mainly enriched in
“cell communication, signal transduction and cell adhesion molecule
activity”, which were closely related to cancer metastasis.
CENPE (Centromere‐associated protein E) is a kinesin‐like motor
protein that accumulates in the G2 phase of the cell cycle. Microarray
analysis showed that CENPE was a crucial upregulated gene in
MA ET AL.
invasive ductal carcinoma (Li, Luo, Wei, & Wang, 2018), which was
also elevated in basal‐a molecular subtype triple negative breast
cancer and genetic deletion or pharmacological inhibition of CENPE
reduced basal‐a breast cancer cell viability (Kung et al., 2014). The
elevated CENPE is essential to prostate cancer proliferation and
downregulated CENPE significantly decreases tumor growth in vivo
(Liang et al., 2017). In castration‐resistant prostate cancer cells, the
reprogramming of the binding of lysine‐specific demethylase 1A
resulted in an increase of AR binding at the CENPE promoter and
subsequently enhanced CENPE transcription (Liang et al., 2017). In
Hela cells, XAB2 interacted with CENPE promoter and regulated by
XAB2 on the transcriptional level. These results suggest that
epigenetic regulation might be a mechanism of CENPE dysregulation
in cancer cells (Hou et al., 2016).
Non‐SMC condensin I complex subunit H (NCAPH) is one of the
three non‐SMC subunits in Condensin I, which belongs to a recently
defined superfamily of proteins termed kleisins (Neuwald & Hirano,
2000). Microarray analysis showed that NCAPH was highly expressed
in serous ovarian cancer (SOC) and contributed to carboplatin
resistance in SOC patients (Zhan, Liu, & Linghu, 2018). The functional
study revealed that NCAPH knockdown promotes HCT116 and
SW480 cell apoptosis and cell cycle arrest at G2/M phase, and
depletion of NCAPH inhibited HCT116 cell proliferation, migration in
MA ET AL.
vitro and xenograft tumor formation in vivo (Yin et al., 2017).
Mechanistically, antitumor miR‐199a/b‐3p could inhibit NCAPH
expression by binding the 3′‐untranslated region of NCAPH in PC3
and C4‐2 prostate cancer cells (Arai et al., 2019). These results
elucidated that NCAPH might be played an important role in
tumorigenesis and could be used as a therapeutic target for
colorectal cancer patients.
Alpha‐2‐macroglobulin (A2M) is a protease inhibitor and cytokine
transporter encoded gene. A2M was found to inhibit the malignant
properties of astrocytoma cells by impeding β‐catenin signaling (Lindner
et al., 2010). Moreover, A2M modulated tumor cell adhesion, migration,
and growth by inhibiting tumor‐promoting signaling pathways and
upregulated PTEN via downregulation of miR‐21, in vitro and in tumor
xenografts (Kurz et al., 2017). These studies showed that A2M might be
used as a novel therapeutic target. In human vascular smooth muscle
cells, MMP activity was upregulated by NR4A receptors through
directly binding to A2M promoter (Rodriguez‐Calvo et al., 2015). For
this reason, A2M might be associated with tumor metastasis due to
MMP, a significant contributor to cell invasion. Hydroxysteroid 17‐beta
dehydrogenase 6 (HSD17B6) is a protein which has both oxidoreduc-
tase and epimerase activities and is involved in androgen catabolism.
HSD17B6 mRNA levels in castration‐resistant prostate cancer bone
metastatic samples were significantly lower than that in nonmetastatic
cancer samples (Jernberg et al., 2013). Moreover, HSD17B6, a key
enzyme of oxidative 3α‐HSD that catalyzes the conversion of 3α‐diol to
dihydrotestosterone in prostate cancer cells, was overexpressed in
prostate cancer patients who received androgen deprivation therapy
than that in tissues of untreated individuals. These results showed that
HSD17B6 dysfunction involved in prostate cancer metastases and drug
resistance. Leucine‐rich repeat kinase 2 (LRRK2) is a multidomain
cytoplasmic protein including a leucine‐rich repeat toward the N‐
terminal (LRR), a kinase domain at the C‐terminal (MAPK), and a Roc
(Ras of Complex proteins) domain which encodes a GTPase, and a COR
(C‐terminal of Roc) domain (Gilsbach & Kortholt, 2014). LRRK2 was
associated with a formidable antitumor activity such as suppression of
proliferation, migration, and invasion of tumor cells, and induction of
apoptosis along with the arrest of the cell cycle (Madero‐Perez et al.,
2018). Bioinformatics analysis also showed that LRRK2 was a hub gene
of colon cancer (Peng et al., 2018) and exhibited important role in Lung
squamous cell carcinoma and Lung adenocarcinoma (Meng, Zhang, Ren,
& Ma, 2019). Myosin heavy chain 11 (MYH11) functions as a contractile
protein, converting chemical energy into mechanical energy through
ATP hydrolysis. MYH11 locates on 16P13.11, in 5% to 10% of de novo
acute myeloid leukemia harboring an inv(16)(p13q22) or t(16;16)
(p13;q22) that formed oncogenic fusion CBFB/MYH11 (Douet‐Guilbert
et al., 2017). In solid tumors, mutations of MYH11 were also easy to see
(Jo, Kim, Yoo, & Lee, 2018). Furthermore, RNA‐seq data also showed
that MYH11 was a critical gene of colon adenocarcinoma (Xi et al.,
2017).
Besides, the aforementioned two upregulated genes and four
downregulated genes were first identified differentially expressed in
NSCLC patients. We found that all the selected hub genes were
associated with clinical stages except MYH11, and only the
| 9
upregulated gene CENPE was contributed to worse OS. Moreover,
we also found that the upregulated DEGs were mainly enriched in
“Spindle assembly”, “Microtubule”, “Kinetochore”, and “Metalloendo-
peptidase activity”, which could be used as chemotherapeutic targets
for cancer treatment (Cui, Tang, Tan, & Hu, 2018; Li, Gu et al., 2018;
Li, Zhang et al., 2018; Marques, Fonseca, Silva, & Bousbaa, 2015;
Prahl et al., 2018). Furthermore, the downregulated DEGs were
mainly enriched in “Cell communication”, “Signal transduction”,
“plasma membrane”, “Extracellular”, and “Cell adhesion molecule
activity”, which were also correlated to tumorigenesis or tumor
progression (Iqbal, Alkarim, AlHejin, Mukhtar, & Saini, 2016; Lin, Wu,
Yeh, & Lin, 2018; Toth et al., 2018). These results demonstrated that
these hub genes might be contributed to cancers, including NSCLC.
In the present study, we identified CENPE, NCAPH, MYH11,
LRRK2, HSD17B6, and A2M as hub genes in NSCLC, and the functions
of these genes in NSCLC are needed to excavate deeply. At present,
some studies had identified the key genes through microarray
datasets in NSCLC patients (Li, Gu et al., 2018; Li, Zhang et al., 2018;
Liu et al., 2016; Shi et al., 2017). The major difference between the
present study and previous studies is the discovery of the six
uncovered genes in NSCLC. Besides that, the population of the
selected microarray datasets included Spanish, Australian, African
Americans, and European Americans, which could more representa-
tive than others. Nevertheless, there are still some limitations in our
study, such as we did not validate the hub genes in Chinese NSCLC
patients, as well as lack of the related mechanism study. Further
studies need to be done to confirm whether these genes contributed
to tumorigenesis or could be used as therapeutic targets in NSCLC.
In conclusion, our study provided a comprehensive bioinformatics
analysis of DEGs, which might contribute to the tumorigenesis or
progression of NSCLC patients. Further studies are needed to clarify
the exact molecular mechanisms of these hub genes in NSCLC.
AC KNO WL EDG M EN TS
The authors thank Nanchong Key Laboratory of Molecular Diagnosis
and Therapeutics of Tumor, for providing the research platform of
the current study. The authors acknowledge the financial support
from the Scientific Research Fund of Sichuan Provincial Health and
Family Planning Commission (grant no. 16PJ131 and 17PJ588), and
the Science and Technology Support Program of Nanchong (grant no.
16YFZJ0133, NCKL201703, and 18SXHZ0579).
CON F LI CT OF IN TE RES T
The authors declare that there is no conflict of interest.
AU TH OR CO NTRIB UTION S
Q. M. and Y. X. designed the study. Q. M., H. L., D. X., C. L., and W. P.
contributed to the literature search. Y. X., Y. C. and L. X. performed
this study. Q. M. and Y. X. wrote the initial draft of the manuscript. X.
10 | MA
Z. and X. G. reviewed and edited the manuscript. All authors read and
approved the manuscript.
OR CID
Xiaolan Guo http://orcid.org/0000-0003-4591-0676
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How to cite this article: Ma Q, Xu Y, Liao H, et al.
Identification and validation of key genes associated with
non‐small‐cell lung cancer. J Cell Physiol. 2019;1–11.
https://doi.org/10.1002/jcp.28839