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Abstract

BACKGROUND:

Gastric cancer is the third leading cause of cancer-related deaths worldwide.

OBJECTIVE:

The present study aims to identify key long non-coding RNAs (lncRNAs) and their potential roles in the pathogenesis of gastric adenocarcinoma.

METHODS:

The lncRNA and mRNA expression profile between gastric adenocarcinoma and adjacent non-tumor tissues were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between gastric adenocarcinoma and adjacent non-tumor tissues were identified after bioinformatics analysis. DElncRNA-DEmRNA co-expression network and DElncRNA-nearby DEmRNA interaction network were constructed, respectively. Functional annotation for DEmRNAs interacted with DElncRNAs was performed. Receiver operating characteristic (ROC) analysis of selected DElncRNAs was conducted.

RESULTS:

Based on TCGA, the mRNA and lncRNA expression profiles of 375 gastric adenocarcinoma and 32 adjacent non-tumor tissues were downloaded. A total of 1502 DEmRNAs and 928 DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues were identified. HOXC-AS3 might involve with gastric adenocarcinoma by regulating a set of HOX genes (HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13) with cis-effect. AC115619.1-APOA4/APOB and AP006216.2-APOA1/APOA4 integrations might play roles in gastric adenocarcinoma through regulating pathways of Fat digestion and absorption and Vitamin digestion and absorption. Six lncRNAs including (HOTAIR, C20orf166-AS1, PGM5-AS1, HOXC-AS3, HOXC-AS2 and AC012531.1) have excellent diagnostic value for gastric adenocarcinoma.

CONCLUSIONS:

This study identifies key lncRNAs in gastric adenocarcinoma which provides clues for exploring the pathogenesis and developing potential biomarkers for gastric adenocarcinoma.

Keywords

Gastric adenocarcinoma The Cancer Genome Atlas (TCGA)long non-coding RNAs (lncRNAs)mRNA biomarker

1. Introduction

Gastric cancer is one of the most common types of cancers that is the third leading cause of cancer-related death worldwide [1]. The incidence rate of gastric cancer is particularly high in East Asia and South America [2]. Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer. Due to delayed diagnosis, the five- year survival rate of patients with gastric cancer is low [1]. Although the strongest risk factor for gastric cancer, Helicobacter pylori infection, has been identified, and the mechanism of carcinogenesis is complex and poorly understood. Hence, it is critical to explore the pathogenesis and develop accurate biomarkers for gastric cancer.

Table 1
Patient characteristic

Index	Patients with gastric adenocarcinoma ( $n=$ 375)
Gender
female	134
male	241
Age (years)
$>$ 60	250
$\leqslant$ 60	121
Not available	4
Race
Asian	74
Black or African American	11
Native Hawaiian or Other Pacific Islander	1
White	238
Not available	37
Not evaluated	2
Unknown	12
Ethnicity
Hispanic or Latino	5
Not Hispanic or Latino	269
Not available	37
Not evaluate	60
Unknown	4
Grade
G1	10
G2	137
G3	219
GX	9
Stage
Stage I	2
Stage IA	14
Stage IB	37
Stage II	27
Stage IIA	35
Stage IIB	49
Stage III	3
Stage IIIA	60
Stage IIIB	52
Stage IIIC	35
Stage IV	38

Table 2

Top 20 up- and down-regulated DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues

DElncRNA ID	DElncRNA symbol	log2 fold-change	FDR	Regulation
ENSG00000229967	MAGEA4-AS1	9.631945	1.36E-19	Up
ENSG00000228437	LINC02474	6.687017	8.30E-22	Up
ENSG00000249550	LINC01234	6.649405	4.07E-36	Up
ENSG00000251151	HOXC-AS3	6.500281	8.65E-31	Up
ENSG00000228295	LINC00392	6.44861	2.12E-10	Up
ENSG00000225548	LINC01980	6.298557	1.42E-15	Up
ENSG00000250920	AC105460.1	5.973242	1.22E-12	Up
ENSG00000251026	LINC02163	5.957161	2.51E-28	Up
ENSG00000227932	SELENOOLP	5.850855	1.23E-11	Up
ENSG00000266602	AC008109.1	5.749083	1.67E-12	Up
ENSG00000224271	LOC284930	5.651569	2.51E-18	Up
ENSG00000250874	AC010595.1	5.487742	3.88E-12	Up
ENSG00000228630	HOTAIR	5.445323	2.50E-38	Up
ENSG00000248131	LINC01194	5.351097	7.04E-09	Up
ENSG00000249196	TMEM132D-AS1	5.269798	2.57E-10	Up
ENSG00000253363	AC090809.1	5.251797	2.41E-09	Up
ENSG00000229970	LOC100505938	5.213602	4.47E-35	Up
ENSG00000259485	LINC02253	5.19951	9.72E-15	Up
ENSG00000227674	LINC00355	5.190495	7.79E-14	Up
ENSG00000197085	NPSR1-AS1	5.182875	1.13E-26	Up
CTD $-$ 2331C18.5	CTD $-$ 2331C18.5	$-$ 6.15548	0.000125	Down
ENSG00000261012	AC115619.1	$-$ 5.36464	6.15E-07	Down
ENSG00000260402	AC133485.2	$-$ 4.88801	0.000129	Down
ENSG00000257935	LHX5-AS1	$-$ 4.83369	4.61E-08	Down
ENSG00000273225	FAM25BP	$-$ 4.68231	4.89E-08	Down
ENSG00000228789	HCG22	$-$ 4.66404	3.16E-15	Down
ENSG00000250298	GIMD1	$-$ 4.64117	1.65E-05	Down
ENSG00000233342	AL391361.3	$-$ 4.63105	9.39E-07	Down
ENSG00000241224	C3orf85	$-$ 4.62346	9.63E-17	Down
ENSG00000223914	LINC02471	$-$ 4.58835	2.13E-09	Down
ENSG00000232328	AC084030.1	$-$ 4.28432	5.35E-06	Down
ENSG00000256513	AC022081.1	$-$ 4.2156	2.57E-07	Down
ENSG00000253701	ENSG00000253701	$-$ 4.0754	4.45E-20	Down
ENSG00000216560	LINC00955	$-$ 4.06633	1.58E-08	Down
ENSG00000233005	AC018742.1	$-$ 3.9889	1.47E-17	Down
ENSG00000233850	AC103563.7	$-$ 3.77222	1.32E-12	Down
ENSG00000198491	LOC101929106	$-$ 3.73367	3.42E-08	Down
ENSG00000235584	LOC101926959	$-$ 3.73128	4.64E-07	Down
ENSG00000234756	LOC105378325	$-$ 3.69449	8.44E-08	Down
ENSG00000260581	LOC105378231	$-$ 3.67242	2.74E-12	Down

DElncRNA, differentially expressed long non-coding RNA between gastric adenocarcinoma and adjacent non-tumor tissues. log2 fold-change, log2-transformed fold-change of DElncRNA expression in gastric adenocarcinoma tissues relative to adjacent non-tumor tissues. FDR, false discovery rate. Regulation, the trend of DElncRNA expression in gastric adenocarcinoma tissues compared with adjacent non-tumor tissues.

Long non-coding RNA (lncRNA) is a new class of non-coding RNA with transcripts more than 200 bp in length, which has been receiving increased attention [3]. Through cis- or transacting mechanisms, lncRNAs could regulate gene expression at transcriptional, epigenetic, and translative levels [4, 5]. Accumulated evidences indicated that abnormal expressed lncRNAs play roles in the occurrence and progression of tumors [6, 7]. Moreover, several gastric cancer-related lncRNAs including MEG3, DANCR, SNHG7, HOXA11-AS, HOTAIR and HOXC-AS3 have been identified [8, 9, 10, 11, 12, 13], which highlighted the importance of lncRNAs in gastric cancer.

In the present study, we identify differentially expressed lncRNAs (DElncRNAs) and mRNA (DEmRNAs) between GAC and adjacent non-tumor tissues based on The Cancer Genome Atlas (TCGA) and bioinformatic analysis. Furthermore, functional annotation of DEmRNAs interacted with DElncRNAs contributes to exploring function of DElncRNAs in GAC. In addition, several lncRNAs indicate excellent diagnostic value for GAC. Our study provides clues for better understanding of pathogenesis and developing novel biomarkers for GAC.

2. Materials and methods

2.1 mRNA and lncRNA expression profiles of GAC in TCGA

The Cancer Genome Atlas (TCGA) is a central bank for multi-dimensional data of various cancers at DNA, RNA and protein levels. In this study, the clinical data of patients with GAC were downloaded from TCGA data portal (http://tcga-data.nci.nih.gov/). The mRNA and lncRNA expression profiles between GAC and adjacent non-tumor tissues were downloaded from TCGA data portal (http://tcga-data.nci.nih.gov/) as well.

2.2 Identification of DElncRNAs and DEmRNAs between GAC and adjacent non-tumor tissues

DElncRNAs and DEmRNAs between GAC and adjacent non-tumor tissues were calculated via R package DESeq2 (http://bioconductor.org/packages/DESe q2/). False discovery rate (FDR) was obtained by multiple comparisons using Benjamini and Hochberg method. FDR $<$ 0.05 and $|$ Log ${}_{2}$ fold change $|>$ 2 were served as the threshold for the expression of both DElncRNAs and DEmRNAs. Hierarchical clustering analysis of DElncRNAs and DEmRNAs were conducted by using R package “pheatmap” (https://CRAN.R- project.org/package=pheatmap).

2.3 DElncRNA-DEmRNA co-expression analysis

The pairwise Pearson correlation coefficients between DElncRNAs and DEmRNAs were calculated. DElncRNA-DEmRNA pairs with $|r|>$ 0.8 and $p$ -value $<$ 0.05 were defined as significantly co-express- ed DElncRNA-DEmRNA pairs and retained for our following research. The DElncRNA-DEmRNA co-expre-ssion network was constructed by using Cytoscape software (http://www.cytoscape.org/).

2.4 DElncRNA-nearby DEmRNA interaction analysis

LncRNAs were reported to regulate genes that were transcribed near them, consistent with activity in cis [14]. To identify the nearby DEmRNAs of DElncRNAs with cis-regulatory effects, DEmRNAs transcribed within a 10kb/100kb window up-or down-stream of DElncRNAs between patients with GAC and adjacent non-tumor tissues were searched. The DElncRNA-nearby DEmRNAs interaction network was constructed by using Cytoscape software (http://www.cytoscape.org/).

2.5 Functional annotation

Functional annotation including Gene ontology(GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) molecular pathway enrichment analysis was performed for DEmRNAs co-expressed with DElncRNAs and nearby DEmRNAs of DElncRNAs using DAVID 6.8 (https://david.ncifcrf.gov/). Statistical significance was defined as $p$ -value $<$ 0.05.

Figure 1.

Hierarchical clustering analysis of DElncRNAs and DEmRNAs between gastric adenocarcinoma and adjacent non-tumor tissues. A). DElncRNAs; B). DEmRNAs GAC, gastric adenocarcinoma. Row and column represented DElncRNAs/DEmRNAs and tissue samples, respectively. The color scale indicated the expression of DElncRNAs and DEmRNAs. Red and green color indicated up- and down-regulation, respectively.

Figure 2.

DElncRNA-DEmRNA co-expression network. Red and green ellipses represent up- and down-regulated DEmRNAs between gastric adenocarcinoma and adjacent non-tumor tissues, respectively. Orange and blue rectangles represent up- and down-regulated DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues, respectively. Edges indicate DElncRNA-DEmRNA co-expression. DEmRNAs, differentially expressed mRNAs. DElncRNAs, differentially expressed lncRNAs.

Figure 3.

Pathway of fat digestion and absorption. The red rectangles represented the particles which regulated by DEmRNAs between gastric adenocarcinoma and adjacent non-tumor tissues

Figure 4.

Pathway of vitamin digestion and absorption. The red rectangles represented the particles which regulated by DEmRNAs between gastric adenocarcinoma and adjacent tissues.

2.6 ROC (receiver operating characteristic) analysis

In order to access the diagnostic value of DElncRNAs for GAC, the “pROC” package (https://CRAN. R-project.org/package=pROC) was used to calculate ROC, and the area under the ROC curve (AUC) was further calculated. DElncRNAs and DEmRNAs with AUC $>$ 0.8 were considered capable of distinguishing patients with GAC and normal controls with excellent specificity and sensitivity.

3. Results

3.1 DEmRNAs and DElncRNAs between GAC and adjacent non-tumor tissues

The clinical data of 375 patients with GAC and the mRNA and lncRNA expression profiles of 375 GAC tumor tissues and 32 adjacent non-tumor tissues were downloaded from TCGA. Detailed information of these 375 patients with GAC was displayed in Table 1. A total of 928 DElncRNAs (684 up-regulated and 244 down-regulated lncRNAs) and 1502 DEmRNAs (685 up-regulated and 817 down-regulated mRNAs) between GAC and adjacent non-tumor tissues were identified with FDR $<$ 0.05 and $|$ Log2 fold change $|>$ 2. The top 20 up- and down-regulated DElncRNAs and DEmRNAs were displayed in Table 2 and Table 3, respectively. Hierarchical clustering analysis of DElncRNAs and DEmRNAs was displayed in Fig. 1A and Fig. 1B, respectively. The volcano plots of DElncRNAs and DEmRNAs were shown in Supplemental Figure S1.

Table 3
Top 20 up- and down-regulated DEmRNAs between gastric adenocarcinoma and adjacent non-tumor tissues

Gene ID	Gene symbol	log2 fold-change	FDR	Regulation
4111	MAGEA12	9.281521	5.57E-30	Up
4103	MAGEA4	8.923382	6.37E-19	Up
4105	MAGEA6	8.884978	1.68E-26	Up
4102	MAGEA3	8.643465	4.89E-28	Up
3228	HOXC12	8.459746	4.24E-29	Up
30848	CTAG2	8.364145	1.15E-13	Up
4100	MAGEA1	7.539289	7.05E-15	Up
51438	MAGEC2	7.38416	2.21E-11	Up
1469	CST1	7.120095	2.13E-72	Up
84677	DSCR8	7.023158	4.03E-14	Up
1300	COL10A1	6.975518	1.98E-83	Up
4109	MAGEA10	6.853706	3.88E-14	Up
158511	CSAG1	6.839782	1.00E-27	Up
3381	IBSP	6.770458	4.02E-35	Up
9947	MAGEC1	6.583825	1.11E-11	Up
3226	HOXC10	6.558479	1.04E-51	Up
250	ALPP	6.455339	1.14E-33	Up
23532	PRAME	6.324011	8.17E-35	Up
9965	FGF19	6.260442	5.47E-25	Up
570	BAAT	6.182022	9.39E-36	Up
54544	CRCT1	$-$ 5.405643	2.16E-08	Down
7021	TFAP2B	$-$ 5.445648	1.54E-24	Down
345	APOC3	$-$ 5.494127	2.42E-13	Down
653808	ZG16	$-$ 5.581241	4.57E-29	Down
2695	GIP	$-$ 5.716217	1.11E-21	Down
644414	DEFB131	$-$ 5.733469	2.31E-14	Down
795	S100G	$-$ 5.74117	5.68E-40	Down
1670	DEFA5	$-$ 5.752139	8.88E-10	Down
353145	LCE3E	$-$ 5.766832	6.78E-07	Down
643161	FAM25A	$-$ 5.842917	6.86E-10	Down
3848	KRT1	$-$ 5.895401	1.01E-33	Down
89872	AQP10	$-$ 5.908242	1.83E-30	Down
4225	MEP1B	$-$ 5.941831	1.19E-34	Down
26285	CLDN17	$-$ 6.068541	1.06E-05	Down
2312	FLG	$-$ 6.071618	5.07E-41	Down
5948	RBP2	$-$ 6.100315	1.12E-28	Down
2520	GAST	$-$ 6.409692	3.33E-21	Down
337	APOA4	$-$ 6.49631	7.36E-17	Down
341116	MS4A10	$-$ 6.770715	1.79E-39	Down
339221	ENPP7	$-$ 6.876668	3.27E-52	Down

DEmRNAs, differentially expressed mRNAs between gastric adenocarcinoma and adjacent non-tumor tissues. log2 fold-change, log2-transformed fold-change of gene mRNA expression in gastric adenocarcinoma tissues relative to adjacent non-tumor tissues. FDR, false discovery rate. Regulation, the trend of gene mRNA expression in gastric adenocarcinoma tissues compared with adjacent non-tumor tissues.

Table 4

Nearby DEmRNAs that co-expressed with DElncRNAs

DElncRNA ID	DElncRNA symbol	Gene symbol	Chr	Start	End	$r$	$p$ -value
ENSG00000215023	AC131097.1	GAL3ST2	2	241800916	241801907	0.83609	1.18E-107
ENSG00000223608	DSCR4-IT1	DSCR4	21	38006544	38010618	0.93571	2.28E-185
ENSG00000223774	AL513217.1	LMOD1	1	201893842	201899978	0.82462	2.98E-102
ENSG00000224272	AC131097.3	GAL3ST2	2	241808312	241812016	0.88528	9.79E-137
ENSG00000224958	PGM5-AS1	PGM5	9	68355189	68357852	0.933	7.33E-182
ENSG00000227640	SOX21-AS1	SOX21	13	94712716	94716246	0.95761	5.15E-221
ENSG00000229967	MAGEA4-AS1	MAGEA4	X	151904431	151913968	0.94394	4.88E-197
ENSG00000230316	FEZF1-AS1	FEZF1	7	122303658	122310077	0.86413	7.73E-123
ENSG00000231062	AC103563.2	MAL	2	95051395	95053176	0.82062	1.85E-100
ENSG00000233682	LOC101929122	FNDC1	6	159165899	159170007	0.86708	1.24E-124
ENSG00000233850	AC103563.7	MAL	2	95025193	95026709	0.84471	5.37E-112
ENSG00000233854	POU6F2-AS2	POU6F2	7	38984243	39013551	0.88254	8.66E-135
ENSG00000234638	AC053503.4	DES	2	219425071	219426184	0.87472	1.75E-129
ENSG00000234638	AC053503.4	SPEG	2	219425071	219426184	0.82073	1.65E-100
ENSG00000234695	LOC105375401	GNGT1	7	93890913	93893601	0.8497	1.23E-114
ENSG00000235601	BARX1-DT	BARX1	9	93955597	93959140	0.91372	1.73E-160
ENSG00000235934	AC007405.2	GAD1	2	170816293	170818037	0.86043	1.20E-120
ENSG00000236841	AC007750.1	FAP	2	162159762	162173223	0.82331	1.17E-101
ENSG00000237125	HAND2-AS1	HAND2	4	173527270	173659696	0.96762	2.92E-244
ENSG00000239513	LINC01210	SOX14	3	137771949	137780878	0.84283	5.00E-111
ENSG00000242207	HOXB-AS4	HOXB9	17	48628675	48634932	0.82925	2.21E-104
ENSG00000248362	AC011352.1	C5orf46	5	147886086	147886878	0.83972	1.87E-109
ENSG00000248676	AC083902.1	MTTP	4	99594799	99625913	0.80244	7.68E-93
ENSG00000249641	HOXC13-AS	HOXC13	12	53935328	53939643	0.92114	4.64E-168
ENSG00000250889	LINC01336	GCNT4	5	75047719	75052843	0.87096	4.72E-127
ENSG00000251151	HOXC-AS3	HOXC10	12	53981509	53985519	0.90371	2.72E-151
ENSG00000253308	AC004080.1	EVX1	7	27239243	27241228	0.83608	1.19E-107
ENSG00000253405	EVX1-AS	EVX1	7	27241429	27247229	0.8742	3.89E-129
ENSG00000253508	AC004080.2	HOXA11	7	27186573	27193448	0.83454	6.67E-107
ENSG00000253508	AC004080.2	HOXA13	7	27186573	27193448	0.93333	2.85E-182
ENSG00000253838	AC007991.2	IDO1	8	39914229	39915721	0.89593	8.22E-145
ENSG00000254287	AC007991.4	IDO1	8	39918076	39920890	0.88136	5.81E-134
ENSG00000254933	AP000785.1	WNT11	11	76190725	76195071	0.82364	8.29E-102
ENSG00000256508	MRGPRF-AS1	MRGPRF	11	69012283	69018447	0.82075	1.61E-100
ENSG00000257671	KRT7-AS	KRT7	12	52245048	52247448	0.87512	9.57E-130
ENSG00000257761	AC078860.1	LGR5	12	71582293	71583852	0.8127	4.88E-97
ENSG00000260015	AC010547.2	CHST4	16	71539834	71541825	0.93941	2.09E-190
ENSG00000261012	AC115619.1	APOB	2	20999313	21000917	0.86858	1.47E-125
ENSG00000261146	AC007159.1	SOX14	3	137791973	137796678	0.80495	7.61E-94
ENSG00000261292	AC110491.1	EPHA6	3	97759523	97761532	0.84193	1.43E-110
ENSG00000261616	AC036108.3	SYNM	15	99139317	99145370	0.88152	4.53E-134
ENSG00000263065	AF001548.1	MYH11	16	15741151	15741791	0.89864	5.17E-147
ENSG00000267328	AC002398.2	HSPB6	19	35754566	35755490	0.91393	1.07E-160
ENSG00000268307	LINC02560	RNF225	19	58400221	58400679	0.84268	5.94E-111
ENSG00000268812	LOC91370	LIF	22	30246205	30246998	0.84804	9.55E-114
ENSG00000277268	LHX1-DT	LHX1	17	36861674	36936661	0.8696	3.40E-126

DElncRNA, differentially expressed long non-coding RNAs between gastric adenocarcinoma and adjacent non-tumor tissues. DEmRNAs, differentially expressed mRNAs between gastric adenocarcinoma and adjacent non-tumor tissues. Chr, chromosome location of DElncRNA. Start, start site of DElncRNA location. End, end site of DElncRNA location. $r$ , the Pearson correlation coefficients between the DElncRNA expression and gene mRNA expression.

3.2 DElncRNA-DEmRNA co-expression network

A total of 795 DElncRNA-DEmRNA co-expression pairs including 82 DElncRNAs (47 up-regulated and 35 down-regulated DElncRNAs) and 206 DEmRNAs (48 up-regulated and 158 down-regulated DEmRNAs) were obtained with $|r|>$ 0.8 and $p$ -value $<$ 0.05. Furthermore, all these 795 DElncRNA-DEmRNA pairs were positively co-expressed pairs ( $p$ -value $<$ 0.05 and $r>$ 0.8). Based on the DElncRNA-DEmRNA co-expression network (Fig. 2), PGM5-AS1 (degree $=$ 80), ENSG00000258247 (degree $=$ 76) and C20orf166 -AS1 (degree $=$ 72) were top three DElncRNAs co-expressed with most DEmRNAs which were all down-regulated in the GAC tumor tissues compared to adjacent non-tumor tissues.

3.3 DElncRNA-nearby DEmRNA interaction

A total of 336 DElncRNA-nearby DEmRNA pairs (Supplemental Fig. S2) were obtained, which were consisted of 221 DElncRNAs (135 up-regulated and 86 down-regulated DElncRNAs) and 246 DEmRNAs (119 up-regulated and 126 down-regulated DElncRNAs). Four up-regulated lncRNAs including HOXC13-AS (degree $=$ 6), HOXC-AS2 (degree $=$ 6), HOXC-AS3 (degree $=$ 6) and AC012531.1 (degree $=$ 6) and one down-regulated lncRNA, FLG-AS1 (degree $=$ 6) were top five DElncRNAs own most nearby DEmRNAs.

The intersection of DElncRNA-nearby DEmRNA pairs and DElncRNA-DEmRNA co-expression pairs consisted of 46 DElncRNA-DEmRNA pairs, in which DEmRNAs were not only co-expressed with DElncRNAs but also the nearby DEmRNAs of DElncRNAs (Table 4).

Table 5
Top 30 KEGG pathways for DEmRNAs co-expressed with DElncRNAs and nearby DEmRNAs of DElncRNAs

DEmRNAs co-expressed with DElncRNAs
KEGG pathway	Count	$p$ -value	Genes
hsa00980: Metabolism of xenobiotics by cytochrome P450	27	1.26E-12	CYP3A4, CYP2D6, ADH1B, ADH7, GSTM5, ALDH3A1, UGT1A7, AKR1C2, CBR1, UGT1A3, UGT1A5, ADH4, UGT1A4, AKR7A3, AKR1C1, GSTA1, GSTA2, GSTA3, CYP1A1, SULT2A1, CYP2C9, ALDH3B2, UGT1A1, DHDH, UGT2B17, UGT2B11, UGT2B7
hsa05204: Chemical carcinogenesis	26	6.56E-11	CYP3A4, CYP2C18, ADH1B, ADH7, GSTM5, ALDH3A1, UGT1A7, CBR1, UGT1A3, SULT1A1, UGT1A5, ADH4, UGT1A4, SULT1A2, GSTA1, GSTA2, GSTA3, CYP1A1, SULT2A1, CYP2C9, NAT2, ALDH3B2, UGT1A1, UGT2B17, UGT2B11, UGT2B7
hsa04974: Protein digestion and absorption	25	3.53E-09	COL21A1, SLC15A1, ATP1B2, COL3A1, COL22A1, MME, SLC7A9, ATP1A2, SLC6A19, COL4A6, XPNPEP2, COL4A5, KCNJ13, ACE2, MEP1A, CPA2, MEP1B, PGA3, PGA4, COL1A1, PGA5, CPB1, COL11A1, CPB2, COL10A1
hsa00982: Drug metabolism-cytochrome P450	20	1.01E-07	GSTA1, CYP3A4, GSTA2, GSTA3, CYP2C9, CYP2D6, ADH1B, ALDH3B2, ADH7, UGT1A1, GSTM5, ALDH3A1, UGT1A7, UGT2B17, UGT1A3, UGT1A5, ADH4, UGT1A4, UGT2B11, UGT2B7
hsa00830: Retinol metabolism	19	2.56E-07	CYP3A4, CYP1A1, CYP2C9, CYP2C18, ADH1B, ADH7, UGT1A1, UGT1A7, RDH12, RDH8, UGT2B17, LRAT, UGT1A3, ADH4, UGT1A5, UGT1A4, UGT2B11, BCO1, UGT2B7
hsa00140: Steroid hormone biosynthesis	17	1.27E-06	CYP3A4, HSD3B1, CYP11A1, CYP1A1, CYP11B1, UGT1A1, UGT1A7, AKR1C2, CYP17A1, UGT2B17, UGT1A3, UGT1A5, UGT1A4, UGT2B11, AKR1C1, UGT2B7, CYP19A1
hsa04975: Fat digestion and absorption	13	7.95E-06	MOGAT2, MTTP, ABCG8, APOA4, APOB, ABCG5, CD36, APOA1, PLA2G12B, FABP1, PLA2G2C, FABP2, LIPF
hsa03320: PPAR signaling pathway	16	4.25E-05	OLR1, RXRG, PCK2, MMP1, PCK1, APOA2, APOA1, CD36, SORBS1, PLIN1, APOC3, SLC27A6, FABP4, FABP1, FABP2, FABP7
hsa04976: Bile secretion	16	6.12E-05	SLCO1B7, SULT2A1, ATP1B2, SLC5A1, ADCY5, AQP4, ATP1A2, ABCG2, ABCG8, SLCO1B3, BAAT, ABCG5, SLCO1A2, SLCO1B1, SLC51B, SLC51A
hsa04080: Neuroactive ligand-receptor interaction	38	8.40E-05	CCKAR, GRIK2, TACR2, ADCYAP1R1, GRIK3, NPY2R, GRIK5, AGTR1, ADRB3, GALR1, GRIN2D, GRPR, GRID2, NPFFR1, MC3R, CHRNA1, GHR, HTR1E, GABRD, PTH2R, CCKBR, GABRA3, GABRA5, GRIA4, LEP, ADRB2, GABRR1, GRIA2, GRM8, CHRM2, MLNR, P2RY14, F2, P2RX2, MC2R, NMBR, HTR2C, ADRA1D
hsa04971: Gastric acid secretion	16	1.21E-04	KCNJ16, KCNJ15, CCKBR, ATP4A, ATP1B2, SLC9A4, ATP4B, ADCY5, GAST, PRKCG, ATP1A2, CALML3, KCNE2, CAMK2A, SST, MYLK
hsa00053: Ascorbate and aldarate metabolism	9	3.59E-04	UGT1A7, UGT2B17, UGT1A3, UGT1A5, MIOX, UGT1A4, UGT2B11, UGT1A1, UGT2B7
hsa00040: Pentose and glucuronate interconversions	10	6.24E-04	UGT1A7, UGT2B17, UGT1A3, UGT1A5, AKR1B10, UGT1A4, UGT2B11, UGT1A1, DHDH, UGT2B7
hsa04970: Salivary secretion	16	7.82E-04	KCNMA1, NOS1, ATP1B2, ADCY5, CST2, PRKCG, CST1, ATP1A2, ADRB3, ATP2B2, ADRB2, CALML3, RYR3, CST4, ADRA1D, MUC5B
hsa04512: ECM-receptor interaction	16	8.86E-04	IBSP, TNXB, COL3A1, COL4A6, COL4A5, CHAD, LAMB4, CD36, COMP, ITGA8, LAMC2, COL1A1, THBS2, SV2C, COL11A1, SPP1
hsa00983: Drug metabolism-other enzymes	11	0.00103	CYP3A4, XDH, UGT1A7, UGT2B17, UGT1A3, UGT1A5, UGT1A4, NAT2, UGT2B11, UGT1A1, UGT2B7
hsa04972: Pancreatic secretion	16	0.001787	KCNMA1, CCKAR, CLCA2, CLCA1, CLCA4, ATP1B2, ADCY5, PRKCG, ATP1A2, ATP2B2, SLC26A3, PLA2G12B, CPA2, PLA2G2C, CPB1, CPB2
hsa04911: Insulin secretion	14	0.00564	KCNMA1, GCG, CCKAR, GIP, GPR119, ATP1B2, SLC2A2, ADCYAP1R1, ADCY5, PRKCG, CREB3L3, ATP1A2, CAMK2A, KCNMB1
hsa04261: Adrenergic signaling in cardiomyocytes	20	0.00593	ATP1B2, CACNG8, TNNC1, ADCY5, CACNG6, CACNB2, ATP1A2, TPM2, TNNI3, TPM1, ATP2B2, AGTR1, ADRB2, CALML3, PLN, PPP1R1A, SCN7A, CREB3L3, CAMK2A, ADRA1D
hsa05146: Amoebiasis	16	0.006435	CSF2, COL3A1, CXCL8, ACTN2, PRKCG, COL4A6, COL4A5, C8G, LAMB4, SERPINB2, LAMC2, SERPINB4, SERPINB3, SERPINB13, COL1A1, COL11A1
hsa04973: Carbohydrate digestion and absorption	9	0.007574	G6PC, SLC2A5, ATP1B2, SLC5A1, SLC2A2, SI, MGAM, ATP1A2, LCT

Table 5, continued
DEmRNAs co-expressed with DElncRNAs
KEGG pathway	Count	$p$ -value	Genes
hsa04024: CAMP signaling pathway	24	0.010463	FXYD1, GPR119, ATP1B2, ADCYAP1R1, ADCY5, ATP1A2, GRIA4, TNNI3, MYL9, AMH, ATP2B2, ADRB2, NPY, GRIA2, CALML3, CHRM2, GRIN2D, PLN, MC2R, GHRL, SUCNR1, CREB3L3, CAMK2A, HTR1E
hsa04924: Renin secretion	11	0.01242	KCNMA1, ADRB3, AGTR1, ACE, ADRB2, CLCA2, CLCA1, CLCA4, CALML3, ADCY5, ADCYAP1R1
hsa04020: Calcium signaling pathway	22	0.012659	CCKAR, NOS1, CCKBR, TNNC1, TACR2, PRKCG, ATP2B2, ADRB3, AGTR1, ADRB2, CALML3, CHRM2, GRIN2D, PLN, RYR3, P2RX2, GRPR, CACNA1E, CAMK2A, HTR2C, ADRA1D, MYLK
hsa05414: Dilated cardiomyopathy	13	0.013065	DES, SGCG, CACNG8, TNNC1, ADCY5, PLN, ITGA8, CACNG6, CACNB2, TNNI3, TPM2, TPM1, SGCA
hsa04977: Vitamin digestion and absorption	6	0.015793	APOA4, APOB, APOA1, LRAT, RBP2, GIF
hsa05410: Hypertrophic cardiomyopathy (HCM)	12	0.018702	ACE, DES, SGCG, CACNG8, TNNC1, ITGA8, CACNG6, CACNB2, TNNI3, TPM2, TPM1, SGCA
hsa04614: Renin-angiotensin system	6	0.019054	AGTR1, ACE, ACE2, MME, CMA1, ANPEP
hsa05033: Nicotine addiction	8	0.01918	GABRD, SLC17A8, GABRR1, GRIA2, GABRA3, GRIN2D, GABRA5, GRIA4
hsa04610: Complement and coagulation cascades	11	0.020454	F11, KNG1, F5, FGB, F2, SERPINE1, C4BPA, CFD, CPB2, PLAU, C8G
Nearby DEmRNAs of DElncRNAs
KEGG pathway	Count	$p$ -value	Genes
hsa04975: Fat digestion and absorption	5	6.42E-04	APOA4, APOB, APOA1, PLA2G2C, MTTP
hsa04977: Vitamin digestion and absorption	4	1.39E-03	APOA4, APOB, APOA1, RBP2
hsa04727: GABAergic synapse	5	1.11E-02	GABRD, GNGT1, GABRA3, PRKCG, GAD1
hsa04713: Circadian entrainment	5	1.62E-02	GNGT1, CALML3, RYR3, PRKCG, GRIA4
hsa04723: Retrograde endocannabinoid signaling	5	1.98E-02	GABRD, GNGT1, GABRA3, PRKCG, GRIA4
hsa05143: African trypanosomiasis	3	4.48E-02	APOA1, PRKCG, IDO1

DEmRNAs, differentially expressed mRNAs between gastric adenocarcinoma and adjacent non-tumor tissues. DElncRNAs, differentially expressed lncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues. KEGG, Kyoto Encyclopedia of Genes and Genomes. Count, the number of DEmRNAs that enriched in this KEGG pathway. Genes, gene symbol of DEmRNAs that enriched in this KEGG pathway.

3.4 Functional annotation

The top 15 most significantly enriched GO terms, including “biological process”, “molecular function”, and “cellular component” for DEmRNAs co-expressed with DElncRNAs, as well as nearby DEmRNAs of DElncRNAs, were displayed in Supplemental Table S1 and Supplemental Table S2, respectively. Based on the functional annotation of DEmRNAs co-expressed with DElncRNAs, Digestion (GO: 0007586, $p$ -value $=$ 7.71E-16), Structural molecule activity (GO: 0005198, $p$ -value $=$ 6.45E-12) and Extracellular region (GO: 0005576, $p$ -value $=$ 3.76E-35) were significantly enriched GO terms. Anterior/posterior pattern specification (GO: 0009952, 2.04E-09), Structural molecule activity (GO: 0005198, $p$ -value $=$ 7.63E-06) and Cornified envelope (GO: 0001533, $p$ -value $=$ 5.44E-08) were three significantly enriched GO terms for nearby DEmRNAs of DElncRNAs.

According to the KEGG enrichment analysis (Table 5), Metabolism of xenobiotics by cytochrome P450 (hsa00980, $p$ -value $=$ 1.26e-12), Chemical carcinogenesis (hsa05204, $p$ -value $=$ 6.56E-11), Protein digestion and absorption (hsa04974, $p$ -value $=$ 3.53E-09), Fat digestion and absorption (hsa04975, $p$ -value $=$ 7.95E-06) and Gastric acid secretion (hsa04971, $p$ -value $=$ 1.21E-04) were five pathways that were significantly enriched for DEmRNAs co-expressed with DElncRNAs in GAC. Fat digestion and absorption (hsa04975, $p$ -value $=$ 6.42E-04, Fig. 3), Vitamin digestion and absorption (hsa04977, $p$ -value $=$ 1.39E-03, Fig. 4) and Circadian entrainment (hsa04713, $p$ -value $=$ 1.62E-02) were three significantly enriched pathways for both DEmRNAs co-expressed with DElncRNAs and nearby DEmRNAs of DElncRNAs.

Figure 5.

ROC curves of selected DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues. The ROC curves were used to show the diagnostic ability of these selected DElncRNAs in gastric adenocarcinoma with sensitivity and specificity. The $x$ -axis shows 1-specificity and $y$ -axis shows sensitivity. A). HOTAIR, B). C20orf166-AS1, C). PGM5-AS1, D). HOXC-AS3, E). HOXC-AS2, F). AC012531.1

3.5 ROC curve analysis

ROC curve analyses were conducted to assess the diagnostic value of selected DElncRNAs for GAC. The AUC of every selected DElncRNAs including HOTAIR (0.927), C20orf166-AS1 (0.839), PGM5-AS1 (0.910), HOXC-AS3 (0.902), HOXC-AS2 (0.954) and AC012531.1 (0.916) was more than 0.8 (Fig. 5), which suggested that all these six DElncRNAs had excellent diagnostic value for GAC.

4. Discussion

Although function of most lncRNAs remains largely unknown, lncRNAs have been indicated to involve with the pathogenesis of GAC. The current study identified key DElncRNAs in GAC and further explored their potential roles in GAC by functional annotation of DEmRNAs interacted with them.

Two gastric cancer-related DElncRNAs including HOX transcript antisense intergenic RNA (HOTAIR) and HOXC-AS3, were identified in the present study. HOTAIR is a well-studied lncRNA that regulates gene expression through mediating the modulation of chromatin structure [15]. Up-regulated HOTAIR has been observed in various cancers including colorectal cancer, hepatocellular carcinoma, nasopharyngeal carcinoma and gastric cancer [16, 17, 18, 19]. Furthermore, HOTAIR was demonstrated to play a role in carcinogenesis and progression of gastric cancer by involving with inhibition of apoptosis and promoting invasiveness [12]. HOXC-AS3 was reported to involve with tumorigenesis of gastric cancer, and served as a potential diagnosis and therapy for gastric cancer, which could facilitate cell proliferation and migration of gastric cancer through binding to Y-box-binding protein 1 (YBX1) [13].

In addition, several lncRNAs associated with cancers including HCG22, LINC00355, LINC02471, C20 orf166-AS1 and PGM5-AS1 were found to be aberrantly expressed between GAC and adjacent non-tumor tissues, as well. Decreased HCG22 (HLA complex group 22) expression has been observed in pro-state cancer, head and neck squamous cell carcinoma and oral squamous cell carcinoma, which was associated with poor survival of patients [20, 21, 22]. Aberrantly expressed LINC00355 was found in bladder cancer and involved with tumor stage, lymphatic metastasis, and distant metastasis of colon adenocarcinoma [23, 24]. Up-regulated LINC02471 expression was observed in papillary thyroid carcinoma tissues, which had a potential prognostic value for papillary thyroid carcinoma [25]. The expression of C20orf166-AS1 was down-regulated in prostate cancer tissues compared to normal tissues [26]. PGM5-AS1 were significantly associated with the incidence and development of melanoma and high expression of PGM5-AS1 were associated with poor overall survival for patients with in colorectal cancer [27, 28]. To our knowledge, these five cancer-related lncRNAs (HCG22, LINC00355, LINC02471, C20orf166-AS1 and PGM5-AS1) were firstly found to be differentially expressed between GAC and adjacent non-tumor tissues in this study. And we speculated that these five lncRNAs might involve with GAC, and their precise roles in GAC need further research.

Considering lncRNAs have been indicated to involve with cancer by regulating gene expression with cis- and trans-regulatory mechanisms [29], DElncRNA -DEmRNA co-expression network, DElncRNA-nearby DEmRNA interaction network and functional annotation of DEmRNAs integrated with DElncRNAs were used to explore function of key DElncRNAs in GAC. After these bioinformatic analysis, six HOX genes including HOXC8, HOXC9, HOXC10, HOXC11,HOXC12 and HOXC13 were found to be nearby targets of a GAC-related lncRNA HOXC-AS3. Moreover, HOXC10 was co-expressed with HOXC-AS3 as well. All of these six genes were members of HOX genes and accumulated evidences have indicated that HOX genes played important roles in gastrointestinal cancer [30, 31, 32, 33]. HOXC9 promoted the metastasis and stem cell-like phenotype of gastric cancer cells [33]. HOXC10 promoted cell proliferation and metastasis of gastric cancer through MAPK pathway and NF- $\kappa$ B pathway [31, 32]. Hence, HOXC-AS3 might play key roles in GAC by regulating HOX genes. Based on the DElncRNA-DEmRNA co-expression network, two above-mentioned cancer-related lncRNAs (PGM5-AS1 and C20orf166-AS1) are proved hub lncRNAs, and both of them have great diagnostic value for GAC, which emphasized their importance in GAC.

Functional annotation indicated that Fat digestion and absorption (hsa04975) and Vitamin digestion and absorption (hsa04977) were two pathways enriched for both nearby DEmRNAs of DElncRNAs and DEmRNAs co-expressed with DElncRNAs, which highlighted that aberrantly expressed lncRNAs in GAC might involve with GAC by regulating expression of genes enriched in these two pathways. Three genes including APOA1, APOA4 and APOB were enriched for both of the two pathways. APOA1 and APOA4 encode apolipoprotein A1 (ApoA1) and apolipoprotein A4 (ApoA4), respectively, which are major constituents of high-density lipoprotein. While APOB encodes apolipoprotein B (APOB) that is the main apolipoprotein of chylomicrons and low-density lipoproteins. Recently, study indicated that ApoB/ApoA1 ratio could act as an independent prognostic factor in gastric cancer [34]. Moreover, both APOA4 and APOB were co-expressed with a same lncRNA, AC115619.1. APOB was a nearby target of AC115619.1, and APOA1 and APOA4 were nearby targets of AP006216.2. Therefore, AC115619.1-APOA4/APOB and AP006216.2-APOA1/APOA4 integrations were speculated to play vital roles in GAC by mediating Fat digestion and absorption and Vitamin digestion and absorption.

In addition, another two lncRNAs including HOXC-AS2 and AC012531.1 have great diagnostic value for GAC, which may serve as potential biomarkers for GAC. ETV6 (ets translocation variant gene 6) encodes a transcriptional repressor, and involves in various cancers-related translocations, such as acute myeloid leukemia and gastrointestinal stromal tumor [35, 36]. In pediatric acute myeloid leukemia, HOXC-AS2 was found to be a translocation partner of ETV6 and ETV6-HOXC-AS2 fusion may result in a loss of function of ETV6 or HOXC-AS2 [37]. We make a hypothesis that ETV6-HOXC-AS2 fusion might play a role in gastric cancer as well. AC012531.1 is a novel lncRNA that has never been reported, and further research is needed to explore its biological function in GAC.

Taken together, the present study identified key lncRNAs in GAC and further explored their potential roles in GAC by functional annotation of their integrated DEmRNAs. Five lncRNAs (HCG22, LINC003 55, LINC02471, C20orf166-AS1 and PGM5-AS1) associated with other cancers are potential regulators of GAC, as well. Six lncRNAs including (HOTAIR, C20orf166-AS1, PGM5-AS1, HOXC-AS3, HOXC-AS2 and AC012531.1) may serve as potential biomarkers for GAC. A GAC-related lncRNA, HOXC-AS3 might involve with GAC by regulating a set of HOX genes (HOXC8, HOXC9, HOXC10, HOXC11, HOXC 12 and HOXC13) with cis-effect. AC115619.1-APOA4 /APOB and AP006216.2-APOA1/APOA4 integrations are speculated to play roles in GAC through regulating Fat digestion and absorption and Vitamin digestion and absorption. This present study provides new clues for exploring the mechanism and developing diagnostic and therapeutic strategies for GAC. Further experiments are needed to confirm our conclusion.

Footnotes

Supplementary data

The supplementary files are available to download from http://dx.doi.org/10.3233/CBM-192389.

References

Liu

Zhu

Han

Xiao

Jia

and Wang

, ceRNA network construction and comparison of gastric cancer with or without Helicobacter pylori infection, Journal of Cellular Physiology (2018).

Siegel

R.L.

Miller

K.D.

and Jemal

, Cancer statistics, 2016, CA: A Cancer Journal for Clinicians (2016), 7–30.

Ponting

C.P.

Oliver

P.L.

and Reik

, Evolution and functions of long noncoding RNAs, Cell (2009), 629–641.

Rinn

J.L.

and Chang

H.Y.

, Genome regulation by long noncoding RNAs, Annual Review of Biochemistry (2012), 145–166.

Wang

K.C.

and Chang

H.Y.

, Molecular mechanisms of long noncoding RNAs, Molecular Cell (2011), 904–914.

Farhangian

Jahandoost

Mowla

S.J.

and Khalili

, Differential expression of long non-coding RNA SOX2OT in gastric adenocarcinoma, Cancer Biomarkers: Section A of Disease Markers (2018), 221–225.

Egranov

S.D.

Yang

and Lin

, Molecular mechanisms of long noncoding RNAs-medicated cancer metastasis, Genes, Chromosomes & Cancer (2018).

Wei

G.H.

and Wang

, lncRNA MEG3 inhibit proliferation and metastasis of gastric cancer via p53 signaling pathway, European Review for Medical and Pharmacological Sciences (2017), 3850–3856.

Mao

Cui

Xing

Zhao

and Zai

, LncRNA DANCR promotes migration and invasion through suppression of lncRNA-LET in gastric cancer cells, Bioscience Reports (2017).

10.

Wang

M.W.

Liu

Q.H.

T.F.

Jin

and Xia

T.S.

, LncRNA SNHG7 promotes the proliferation and inhibits apoptosis of gastric cancer cells by repressing the P15 and P16 expression, European Review for Medical and Pharmacological Sciences (2017), 4613–4622.

11.

Sun

Nie

Wang

Zhang

Hou

Xie

Wang

and Wang

, LncRNA HOXA11-AS promotes proliferation and invasion of gastric cancer by scaffolding the chromatin modification factors PRC2, LSD1, and DNMT1, Cancer Research (2016), 6299–6310.

12.

Lee

N.K.

Lee

J.H.

Park

C.H.

Lee

Y.C.

Cheong

J.H.

Noh

S.H.

and Lee

S.K.

, Long non-coding RNA HOTAIR promotes carcinogenesis and invasion of gastric adenocarcinoma, Biochemical and Biophysical Research Communications (2014), 171–178.

13.

Zhang

Chen

Yin

Han

and De

, A novel long noncoding RNA HOXC-AS3 mediates tumorigenesis of gastric cancer by binding to YBX1, Genome Biology (2018), 154.

14.

Bonasio

and Shiekhattar

, Regulation of transcription by long noncoding RNAs, Annual Review of Genetics (2014), 433–455.

15.

C.H.

and Chen

, Targeting long non-coding RNAs in cancers: Progress and prospects, The International Journal of Biochemistry & Cell Biology (2013), 1895–1910.

16.

Endo

Shiroki

Nakagawa

Yokoyama

Tamai

Yamanami

Fujiya

Sato

Yamaguchi

Tanaka

Iijima

Shimosegawa

Sugamura

and Satoh

, Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer, PloS One (2013), e77070.

17.

Geng

Y.J.

Xie

S.L.

and Wang

G.Y.

, Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression, The Journal of International Medical Research (2011), 2119–2128.

18.

Kogo

Shimamura

Mimori

Kawahara

Imoto

Sudo

Tanaka

Shibata

Suzuki

Komune

Miyano

and Mori

, Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers, Cancer Research (2011), 6320–6326.

19.

Nie

Liu

Song

Zou

and Gong

, Long non-coding RNA HOTAIR is an independent prognostic marker for nasopharyngeal carcinoma progression and survival, Cancer Science (2013), 458–464.

20.

Jiang

Guo

Zhao

and Miao

, Identification of potential prostate cancer-related pseudogenes based on competitive endogenous RNA network hypothesis, Medical Science Monitor: International Medical Journal of Experimental and Clinical Research (2018), 4213–4239.

21.

Zhao

and Wu

, How long non-coding rnas and micrornas mediate the endogenous RNA network of head and neck squamous cell carcinoma: A comprehensive analysis, Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology (2018), 332–341.

22.

Feng

Houck

J.R.

Lohavanichbutr

and Chen

, Transcriptome analysis reveals differentially expressed lncRNAs between oral squamous cell carcinoma and healthy oral mucosa, Oncotarget (2017), 31521–31531.

23.

Zhang

Qian

Wang

Peng

Zhang

Wang

and Sun

, Analysis of lncRNA-associated ceRNA network reveals potential lncRNA biomarkers in human colon adenocarcinoma, Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology (2018), 1778–1791.

24.

Seitz

A.K.

Christensen

L.L.

Christensen

Faarkrog

Ostenfeld

M.S.

Hedegaard

Nordentoft

Nielsen

M.M.

Palmfeldt

Thomson

Jensen

M.T.

Nawroth

Maurer

Orntoft

T.F.

Jensen

J.B.

Damgaard

C.K.

and Dyrskjot

, Profiling of long non-coding RNAs identifies LINC00958 and LINC01296 as candidate oncogenes in bladder cancer, Scientific Reports (2017), 395.

25.

Cai

W.Y.

Chen

L.P.

X.J.

and Zhou

Y.Y.

, Role of differentially expressed genes and long non-coding RNAs in papillary thyroid carcinoma diagnosis, progression, and prognosis, Journal of Cellular Biochemistry (2018), 8249–8259.

26.

C.C.

Gan

Zhang

R.Y.

Xue

J.X.

and Ran

L.K.

, Identification of prostate cancer LncRNAs by RNA-Seq, Asian Pacific Journal of Cancer Prevention: APJCP (2014), 9439–9444.

27.

Yan

Tan

Xie

Liu

and Li

, Multiple lncRNAs affect the incidence and development of melanoma, Zhong Nan Da Xue Xue Bao Yi Xue Ban = Journal of Central South University Medical Sciences (2017), 134–138.

28.

Zhu

Guo

and Feng

, Identification of key lncRNAs in colorectal cancer progression based on associated protein-protein interaction analysis, World Journal of Surgical Oncology (2017), 153.

29.

Lin

X.C.

Zhu

Chen

W.B.

Lin

L.W.

Chen

D.H.

Huang

J.R.

Pan

Lin

B.T.

Dai

and Tu

Z.G.

, Integrated analysis of long non-coding RNAs and mRNA expression profiles reveals the potential role of lncRNAs in gastric cancer pathogenesis, International Journal of Oncology (2014), 619–628.

30.

Joo

M.K.

Park

J.J.

and Chun

H.J.

, Impact of homeobox genes in gastrointestinal cancer, World Journal of Gastroenterology (2016), 8247–8256.

31.

Yao

Zhang

Lai

Huang

and Zhu

, HOXC10 promotes gastric cancer cell invasion and migration via regulation of the NF-kappaB pathway, Biochemical and Biophysical Research Communications (2018), 628–635.

32.

Guo

Hou

Deng

and Lyu

, HOXC10 up-regulation promotes gastric cancer cell proliferation and metastasis through MAPK pathway, Chinese Journal of Cancer Research (2017), 572–580.

33.

Peng

Kang

Wan

and Wang

, miR-26a/HOXC9 dysregulation promotes metastasis and stem Cell-Like phenotype of gastric cancer, Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology (2018), 1659–1676.

34.

M.Z.

Yuan

S.Q.

Chen

Y.M.

and Zhou

Z.W.

, Preoperative apolipoprotein B/apolipoprotein A1 ratio: A novel prognostic factor for gastric cancer, OncoTargets and Therapy (2018), 2169–2176.

35.

van Barjesteh

van Waalwijk

D.K.

Spensberger

de Knegt

Tang

Lowenberg

and Delwel

, Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia, Oncogene (2005), 4129–4137.

36.

Wada

Arai

Kure

Peng

W.X.

and Naito

, “Wild type” GIST: Clinicopathological features and clinical practice, Pathology International (2016), 431–437.

37.

Rooij

J.D.

, Molecular genetic aberrations and their prognostic relevance in pediatric acute myeloid leukemia (2016).

Identification of key long non-coding RNAs in gastric adenocarcinoma

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

Table 1 Patient characteristic

2.1 mRNA and lncRNA expression profiles of GAC in TCGA

2.2 Identification of DElncRNAs and DEmRNAs between GAC and adjacent non-tumor tissues

2.3 DElncRNA-DEmRNA co-expression analysis

2.4 DElncRNA-nearby DEmRNA interaction analysis

2.5 Functional annotation

3. Results

3.1 DEmRNAs and DElncRNAs between GAC and adjacent non-tumor tissues

Table 3 Top 20 up- and down-regulated DEmRNAs between gastric adenocarcinoma and adjacent non-tumor tissues

3.3 DElncRNA-nearby DEmRNA interaction

Table 5 Top 30 KEGG pathways for DEmRNAs co-expressed with DElncRNAs and nearby DEmRNAs of DElncRNAs

4. Discussion

Footnotes

Supplementary data

References

Table 1
Patient characteristic

Table 3
Top 20 up- and down-regulated DEmRNAs between gastric adenocarcinoma and adjacent non-tumor tissues

Table 5
Top 30 KEGG pathways for DEmRNAs co-expressed with DElncRNAs and nearby DEmRNAs of DElncRNAs