缺氧相关长链非编码RNA作为肝癌预后预测标志物的潜在价值

doi:10.16288/j.yczz.21-416

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Hereditas(Beijing) ›› 2022, Vol. 44 ›› Issue (2): 153-167.doi: 10.16288/j.yczz.21-416

• Research Article • Previous Articles Next Articles

Prognostic and predictive value of the hypoxia-associated long non-coding RNA signature in hepatocellular carcinoma

Min Cheng^1,³(), Jing Zhang⁴, Pengbo Cao²(), Gangqiao Zhou^1,^2,³()

1. Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
2. State Key Lab of Proteomics, National Center for Protein Sciences at Beijing, Institute of Radiation Medicine, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China
3. Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
4. College of Life Science, Hebei University, Baoding 071002, China

Received:2021-12-02 Revised:2022-01-11 Online:2022-02-20 Published:2022-01-19
Contact: Cao Pengbo,Zhou Gangqiao E-mail:18351990262@139.com;birchcpb@163.com;zhougq114@126.com
Supported by:
Supported by the National Key Research and Development Program of China No(2017YFA0504301);the Major Research Plan of the National Natural Science Foundation of China No(91440206)

Abstract

Abstract:

Hepatocellular carcinoma (HCC) is a common cancer worldwide. Hypoxia is an important feature of solid tumors, including HCC, and is also an important factor involved in malignancy progression. However, the identification of hypoxia-related long non-coding RNA (lncRNAs) and their prognostic value in HCC have not been systematically investigated. The aim of this study is to identify the features based on the hypoxia-related lncRNAs and evaluate their predictive value for HCC prognosis. Based on the integrated analysis of HCC transcriptome data from The Cancer Genome Atlas (TCGA), we had identified 233 potential hypoxia-related lncRNAs. We further evaluated the prognostic value of these lncRNAs and optimally established a 12-lncRNA (AC012676.1, PRR7-AS1, AC020915.2, AC008622.2, AC026401.3, MAPKAPK5-AS1, MYG1-AS1, AC015908.3, AC009275.1, MIR210HG, CYTOR and SNHG3) prognostic risk model. The Cox proportional hazards regression analysis revealed that the hypoxia risk score is a novel independent prognostic predictor for HCC patients, which outperforms the traditional clinical pathological factors. Gene set enrichment analysis (GSEA) showed that the hypoxia risk score reflects the activation of biological features related to cell proliferation and the inactivation of lipid metabolism processes. In summary, we had constructed a risk score model based on 12 hypoxia-related lncRNAs, which might be a promising prognostic predictor for HCC patients and highlight their potential roles in the prevention and treatment of this malignancy.

Key words: hepatocellular carcinoma, hypoxia, long non-coding RNA, prognostic model

Min Cheng, Jing Zhang, Pengbo Cao, Gangqiao Zhou. Prognostic and predictive value of the hypoxia-associated long non-coding RNA signature in hepatocellular carcinoma[J]. Hereditas(Beijing), 2022, 44(2): 153-167.

Figures/Tables 15

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Supplementary Table 1

Supplementary Table 2

Supplementary Table 3

Supplementary Table 4

基因集	基因集大小	NES	P
GO_OXYGEN_BINDING	47	-1.67	0
GO_ARACHIDONIC_ACID_MONOOXYGENASE_ACTIVITY	15	-1.66	0
GO_PEROXISOME_ORGANIZATION	32	-2.00	0.0020
GO_PROTEIN_DEGLYCOSYLATION	21	-1.97	0.0020
GO_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS	32	-1.90	0.0020
GO_SERINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS	41	-1.89	0.0020
GO_2_OXOGLUTARATE_METABOLIC_PROCESS	20	-1.88	0.0020
GO_REGULATION_OF_TRIGLYCERIDE_BIOSYNTHETIC_PROCESS	17	-1.88	0.0020
GO_CELLULAR_AMINO_ACID_CATABOLIC_PROCESS	111	-1.87	0.0020
GO_ALPHA_AMINO_ACID_CATABOLIC_PROCESS	94	-1.87	0.0020
GO_PYRIDOXAL_PHOSPHATE_BINDING	51	-1.86	0.0020
GO_SULFUR_AMINO_ACID_METABOLIC_PROCESS	40	-1.84	0.0020
GO_REGULATION_OF_CHOLESTEROL_METABOLIC_PROCESS	22	-1.84	0.0020
GO_ACYL_COA_DEHYDROGENASE_ACTIVITY	17	-1.82	0.0020
GO_GLYOXYLATE_METABOLIC_PROCESS	27	-1.81	0.0020
GO_REGULATION_OF_MITOCHONDRIAL_FISSION	17	-1.73	0.0020
GO_ENERGY_RESERVE_METABOLIC_PROCESS	72	-1.68	0.0020
GO_BILE_ACID_TRANSMEMBRANE_TRANSPORTER_ACTIVITY	15	-1.66	0.0020
GO_SULFUR_AMINO_ACID_BIOSYNTHETIC_PROCESS	19	-1.86	0.0021
GO_REGULATION_OF_GLUCOSE_METABOLIC_PROCESS	104	-1.80	0.0021
GO_BLOOD_COAGULATION_INTRINSIC_PATHWAY	17	-1.77	0.0021
GO_ORGANIC_HYDROXY_COMPOUND_TRANSPORT	155	-1.67	0.0021
GO_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN_REDUCED_FLAVIN_OR_FLAVOPROTEIN_AS_ONE_DONOR_AND_INCORPORATION_OF_ONE_ATOM_OF_OXYGEN	26	-1.65	0.0021
GO_FATTY_ACYL_COA_BINDING	30	-1.87	0.0039
GO_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_DEHYDROGENASE	18	-1.79	0.0040
GO_BILE_ACID_AND_BILE_SALT_TRANSPORT	31	-1.76	0.0040
GO_GLUCAN_METABOLIC_PROCESS	58	-1.75	0.0040
GO_REGULATION_OF_LIPID_CATABOLIC_PROCESS	50	-1.74	0.0040
GO_CELLULAR_LIPID_CATABOLIC_PROCESS	148	-1.84	0.0041
GO_SMALL_MOLECULE_CATABOLIC_PROCESS	325	-1.83	0.0041
GO_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN	149	-1.75	0.0041
GO_RESPONSE_TO_XENOBIOTIC_STIMULUS	104	-1.74	0.0041
GO_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN_NAD_P_H_AS_ONE_DONOR_AND_INCORPORATION_OF_ONE_ATOM_OF_OXYGEN	36	-1.73	0.0041
GO_BLOOD_COAGULATION_FIBRIN_CLOT_FORMATION	24	-1.73	0.0041
GO_DRUG_TRANSMEMBRANE_TRANSPORT	19	-1.68	0.0041
GO_GLUTAMATE_METABOLIC_PROCESS	28	-1.69	0.0042
GO_ALPHA_AMINO_ACID_METABOLIC_PROCESS	226	-1.80	0.0060
GO_PROTEIN_ACTIVATION_CASCADE	67	-1.78	0.0060

基因集	基因集大小	NES	P
GO_ALDEHYDE_DEHYDROGENASE_NAD_ACTIVITY	19	-1.72	0.0060
GO_ANDROGEN_METABOLIC_PROCESS	30	-1.72	0.0062
GO_TRANSCRIPTION_FACTOR_ACTIVITY_DIRECT_LIGAND_REGULATED_SEQUENCE_ SPECIFIC_DNA_BINDING	48	-1.67	0.0062
GO_BRANCHED_CHAIN_AMINO_ACID_METABOLIC_PROCESS	23	-1.78	0.0079
GO_MANNOSIDASE_ACTIVITY	15	-1.76	0.0079
GO_REACTIVE_NITROGEN_SPECIES_METABOLIC_PROCESS	19	-1.76	0.0079
GO_STEROL_TRANSPORT	50	-1.69	0.0081
GO_GLYCINE_METABOLIC_PROCESS	17	-1.68	0.0082
GO_MONOCARBOXYLIC_ACID_TRANSMEMBRANE_TRANSPORTER_ACTIVITY	45	-1.64	0.0083
GO_STEROID_METABOLIC_PROCESS	232	-1.78	0.0085
GO_S_ADENOSYLMETHIONINE_METABOLIC_PROCESS	18	-1.73	0.010
GO_CELLULAR_AMINO_ACID_BIOSYNTHETIC_PROCESS	91	-1.73	0.010
GO_FATTY_ACID_METABOLIC_PROCESS	287	-1.70	0.010
GO_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY	17	-1.68	0.010
GO_BENZENE_CONTAINING_COMPOUND_METABOLIC_PROCESS	24	-1.68	0.010
GO_REGULATION_OF_GLUCONEOGENESIS	37	-1.81	0.012
GO_ALPHA_AMINO_ACID_BIOSYNTHETIC_PROCESS	75	-1.73	0.012
GO_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS	491	-1.71	0.012
GO_THIOESTER_METABOLIC_PROCESS	83	-1.70	0.012
GO_PROTEIN_LIPID_COMPLEX	39	-1.70	0.012
GO_PLATELET_DENSE_GRANULE	20	-1.71	0.013
GO_ARGININE_METABOLIC_PROCESS	17	-1.66	0.013
GO_CELLULAR_AMINO_ACID_METABOLIC_PROCESS	328	-1.75	0.014
GO_REGULATION_OF_CELLULAR_KETONE_METABOLIC_PROCESS	170	-1.68	0.014
GO_TRICARBOXYLIC_ACID_METABOLIC_PROCESS	37	-1.82	0.016
GO_ASPARTATE_FAMILY_AMINO_ACID_METABOLIC_PROCESS	55	-1.80	0.016
GO_REGULATION_OF_PROTEIN_ACTIVATION_CASCADE	34	-1.76	0.016
GO_NEGATIVE_REGULATION_OF_MITOCHONDRION_ORGANIZATION	39	-1.71	0.016
GO_POSITIVE_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS	20	-1.71	0.017
GO_RESPONSE_TO_MERCURY_ION	15	-1.69	0.017
GO_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS	85	-1.65	0.017
GO_STEROL_HOMEOSTASIS	57	-1.77	0.019
GO_STEROL_METABOLIC_PROCESS	121	-1.71	0.019
GO_REGULATION_OF_LIPOPROTEIN_LIPASE_ACTIVITY	15	-1.64	0.019
GO_MITOCHONDRIAL_MATRIX	406	-1.84	0.020
GO_DICARBOXYLIC_ACID_METABOLIC_PROCESS	99	-1.73	0.020
GO_PROTEIN_HOMOTETRAMERIZATION	59	-1.73	0.020
GO_COMPLEMENT_ACTIVATION	45	-1.67	0.020
GO_POSITIVE_REGULATION_OF_LIPID_CATABOLIC_PROCESS	25	-1.69	0.021
GO_COFACTOR_METABOLIC_PROCESS	329	-1.66	0.024

Supplementary Table 5

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特征	样本量(n=367)	比例(%)
年龄(岁)
> 60	194	52.9
≤ 60	173	47.1
性别
女	119	32.4
男	248	67.6
T分类
T1(< 2厘米)	181	49.3
T2(2~5厘米)	92	25.1
T3(≥ 5厘米)	78	21.3
T4(靠近肝脏的血管和/或器官和/或内脏腹膜侵犯)	13	3.5
NA	3	0.8
N分类
N0(附近的淋巴结没有癌细胞)	249	67.8
N1(肝脏附近淋巴结的癌细胞)	4	1.1
NA	114	31.1
M分类
M0(没有癌细胞已经扩散到肝外的迹象)	264	71.9
M1(癌细胞存在于身体其他器官,如肺部或骨骼)	3	0.8
NA	100	27.3

MTX1	ADORA2B	AK3	ALDOA	ANGPTL4	C20orf20	MRPS17	PGF	PGK1
P4HA1	PFKFB4	PGAM1	PVR	SLC16A1	SLC2A1	TEAD4	TPBG	TPI1
GAPD	GMFB	GSS	HES2	HIG2	IL8	KCTD11	KRT17	PEDS1
PSMA7	PSMB7	PSMD2	PTGFRN	PYGL	RAN	RNF24	RNPS1	RUVBL2
ANLN	VEGF	LOC56901	S100A3	B4GALT2	VEZT	LRP2BP	SIP1	BCAR1
MGC14560	SLC6A10	BMS1L	ANKRD9	MGC17624	SLC6A8	BNIP3	C14orf156	MGC2408
HOMER1	C15orf25	MIF	SMILE	HSPC163	CA12	MRPL14	SNX24	IMP-2
NUDT15	SPTB	KIAA1393	LDHA	LDLR	MGC2654	MNAT1	NDRG1	NME1
COL4A5	CORO1C	CTEN	DKFZP564D166	DPM2	EIF2S1	PAWR	PDZK11	PLAU
PPARD	PPP2CZ	PPP4R1	TFAP2C	TIMM23	TMEM30B	TPD52L2	VAPB	XPO5
ANLN	BNC1	C20orf20	CA9	CDKN3	COL4A6	DCBLD1	ENO1	FAM83B
GNAI1	HIG2	KCTD11	KRT17	LDHA	MPRS17	P4HA1	PGAM1	PGK1
AFARP1	TUBB2	LOC149464	S100A10	AD-003	SLCO1B3	CA9	CDCA4	PLEKHG3
ALDOA	FOSL1	SDC1	SLC16A1	SLC2A1	TPI1	VEGFA

LncRNA	Rho	HR (95% CI)	P	类型
AC004816.1	0.6042	1.83 (1.29~2.60)	0.00076	风险
AC008622.2	0.8633	2.37 (1.66~3.40)	< 0.0001	风险
AC009275.1	0.6005	1.82 (1.28~2.59)	0.00083	风险
AC012676.1	0.7518	2.12 (1.49~3.02)	< 0.0001	风险
AC015908.3	-0.7035	0.49 (0.35~0.71)	0.0001	保护
AC020915.2	0.7523	2.12 (1.48~3.04)	< 0.0001	风险
AC026401.3	0.6128	1.85 (1.30~2.63)	0.00068	风险
AC073573.1	-0.6068	0.55 (0.38~0.78)	0.00093	保护
AC114803.1	0.9514	2.59 (1.81~3.71)	< 0.0001	风险
CYTOR	0.7993	2.22 (1.56~3.18)	< 0.0001	风险
DANCR	0.7093	2.03 (1.43~2.90)	< 0.0001	风险
GIHCG	0.7331	2.08 (1.46~2.97)	< 0.0001	风险
MAFG.DT	0.5451	1.72 (1.22~2.44)	0.0022	风险
MAPKAPK5-AS1	0.9134	2.49 (1.73~2.59)	< 0.0001	风险
MIR210HG	0.7222	2.06 (1.44~2.95)	< 0.0001	风险
MIR4435.2HG	0.6980	2.01 (1.41~2.86)	0.00011	风险
MYG1-AS1	0.5395	1.72 (1.21~2.43)	0.0025	风险
PRR7-AS1	0.8126	2.25 (1.59~3.19)	< 0.0001	风险
SNHG3	0.6218	1.86 (1.31~2.65)	0.00054	风险
TMEM220-AS1	-0.4673	0.63 (0.44~0.89)	0.0089	保护

基因	正义(5′→3′)	反义 (5′→3′)
MIR210HG	TGAGTAGGAACTCTGGGCGA	CCACAATGGGAAGGAGGCAT
HIF1A	AGAGGTTGAGGGACGGAGAT	GCACCAAGCAGGTCATAGGT
TGFB	GTCTCCCAAGGAAAGGTAGG	CTCTTGAGTCCCTCGCATCC
AKT	GCGGCAGGACCGAGC	AGGTCTTGATGTACTCCCCTCG
VEGFA	GTCCTGGAGCGTGTACGTTG	CTTCCGGGCTCGGTGATTTA
ACTIN	AGAGCCTCGCCTTTGCCGAT	AGAGCCTCGCCTTTGCCGAT

Prognostic and predictive value of the hypoxia-associated long non-coding RNA signature in hepatocellular carcinoma

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基因集	基因集大小	NES	P
GO_RETROGRADE_VESICLE_MEDIATED_TRANSPORT_GOLGI_TO_ER	77	2.34	0
GO_NEGATIVE_REGULATION_OF_MITOTIC_CELL_CYCLE	198	1.82	0
GO_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_ PROCESS	146	1.81	0
GO_POSITIVE_REGULATION_OF_CELL_CYCLE_PROCESS	243	1.81	0
GO_NUCLEAR_CHROMOSOME_SEGREGATION	218	1.81	0
GO_TUBULIN_BINDING	263	1.78	0
GO_MICROTUBULE_BASED_MOVEMENT	199	1.77	0
GO_MICROTUBULE	397	1.77	0
GO_SPINDLE_MIDZONE	27	1.81	0.0020
GO_REGULATION_OF_CELL_DIVISION	266	1.80	0.0021
GO_NEGATIVE_REGULATION_OF_ORGANELLE_ORGANIZATION	384	1.77	0.0021
GO_REGULATION_OF_DNA_DEPENDENT_DNA_REPLICATION	41	1.81	0.0040
GO_NUCLEAR_UBIQUITIN_LIGASE_COMPLEX	42	1.81	0.0041
GO_POSITIVE_REGULATION_OF_G1_S_TRANSITION_OF_MITOTIC_CELL_CYCLE	24	1.78	0.0041
GO_CONDENSED_CHROMOSOME	183	1.77	0.0043

基因集	基因集大小	NES	P
GO_RECOMBINATIONAL_REPAIR	70	1.78	0.0063
GO_CONDENSED_CHROMOSOME_CENTROMERIC_REGION	94	1.78	0.0064
GO_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION	51	1.77	0.0064
GO_SPINDLE_ASSEMBLY	68	1.81	0.0081
GO_HETEROCHROMATIN	66	1.77	0.0083
GO_CELL_CYCLE_G2_M_PHASE_TRANSITION	132	1.81	0.0084
GO_MITOTIC_CELL_CYCLE_CHECKPOINT	138	1.80	0.013
GO_SPINDLE_LOCALIZATION	38	1.78	0.014
GO_POSITIVE_REGULATION_OF_CHROMOSOME_SEGREGATION	25	1.77	0.014
GO_MEMBRANE_DISASSEMBLY	46	1.79	0.021
GO_REGULATION_OF_TELOMERE_MAINTENANCE	62	1.81	0.023
GO_CHROMOSOMAL_REGION	310	1.79	0.023
GO_SPLICEOSOMAL_COMPLEX	163	1.78	0.033
GO_RNA_SPLICING	335	1.79	0.038
GO_LIPID_OXIDATION	68	-2.15	0
GO_MICROBODY	132	-2.13	0
GO_FATTY_ACID_CATABOLIC_PROCESS	71	-2.13	0
GO_FATTY_ACID_BETA_OXIDATION	49	-2.10	0
GO_MICROBODY_PART	92	-2.08	0
GO_COENZYME_BINDING	175	-2.07	0
GO_ORGANIC_ACID_CATABOLIC_PROCESS	202	-2.03	0
GO_FLAVIN_ADENINE_DINUCLEOTIDE_BINDING	73	-2.02	0
GO_MICROBODY_MEMBRANE	58	-2.00	0
GO_METHIONINE_METABOLIC_PROCESS	18	-1.99	0
GO_COFACTOR_BINDING	258	-1.97	0
GO_MICROBODY_LUMEN	44	-1.97	0
GO_AMINO_ACID_BETAINE_METABOLIC_PROCESS	18	-1.94	0
GO_LIPID_HOMEOSTASIS	107	-1.89	0
GO_BILE_ACID_METABOLIC_PROCESS	35	-1.89	0
GO_REGULATION_OF_FATTY_ACID_OXIDATION	27	-1.84	0
GO_BILE_ACID_BIOSYNTHETIC_PROCESS	20	-1.82	0
GO_CELLULAR_ALDEHYDE_METABOLIC_PROCESS	83	-1.82	0
GO_ACYLGLYCEROL_HOMEOSTASIS	29	-1.82	0
GO_MONOOXYGENASE_ACTIVITY	91	-1.80	0
GO_DRUG_METABOLIC_PROCESS	39	-1.78	0
GO_POSITIVE_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS	33	-1.78	0
GO_NITROGEN_CYCLE_METABOLIC_PROCESS	15	-1.75	0
GO_STEROID_HYDROXYLASE_ACTIVITY	31	-1.70	0
GO_IRON_ION_BINDING	158	-1.70	0
GO_EPOXYGENASE_P450_PATHWAY	18	-1.69	0

基因集	基因集大小	NES	P
GO_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS	57	-1.77	0.025
GO_QUATERNARY_AMMONIUM_GROUP_TRANSPORT	18	-1.74	0.025
GO_SIGNAL_PEPTIDE_PROCESSING	24	-1.71	0.027
GO_GLUCAN_BIOSYNTHETIC_PROCESS	25	-1.68	0.027
GO_RETROGRADE_TRANSPORT_VESICLE_RECYCLING_WITHIN_GOLGI	23	-1.72	0.028
GO_NAD_BINDING	53	-1.69	0.029
GO_NUCLEOSIDE_BISPHOSPHATE_METABOLIC_PROCESS	37	-1.70	0.030
GO_ENDOCYTIC_VESICLE_LUMEN	17	-1.64	0.030
GO_LIGASE_ACTIVITY_FORMING_CARBON_SULFUR_BONDS	40	-1.65	0.035
GO_TRIGLYCERIDE_RICH_LIPOPROTEIN_PARTICLE	19	-1.65	0.035
GO_ASPARTATE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS	23	-1.66	0.036
GO_COENZYME_A_METABOLIC_PROCESS	17	-1.65	0.041
GO_2_IRON_2_SULFUR_CLUSTER_BINDING	21	-1.65	0.044

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