南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (5): 941-949.doi: 10.12122/j.issn.1673-4254.2024.05.16
裴蓓1(), 张艺1, 魏思源1, 梅语1, 宋标1, 董港1, 温子昂2, 李学军1(
)
收稿日期:
2023-09-25
出版日期:
2024-05-20
发布日期:
2024-06-06
通讯作者:
李学军
E-mail:18356051572@163.com;lixujun0308@126.com
作者简介:
裴 蓓,在读博士研究生,E-mail: 18356051572@163.com
基金资助:
Bei PEI1(), Yi ZHANG1, Siyuan WEI1, Yu MEI1, Biao SONG1, Gang DONG1, Ziang WEN2, Xuejun LI1(
)
Received:
2023-09-25
Online:
2024-05-20
Published:
2024-06-06
Contact:
Xuejun LI
E-mail:18356051572@163.com;lixujun0308@126.com
摘要:
目的 探讨肠上皮化生(IM)的潜在关键致病基因。 方法 收集2022年1月~6月在安徽中医药大学第二附属医院脾胃科就诊的21例IM患者,以及同期在我院体检中心接受胃镜检查的21例健康受试者。对所有参与者均行胃镜及病理检查,收集胃组织样本进行转录组学测序以筛选疾病相关差异基因,并通过生物信息学分析明确其生物学功能。同时采用实时荧光定量PCR对结果进行验证。 结果 通过转录组学测序,最终获得了1373个差异基因,其中827个上调的mRNA和546个下调的mRNA。根据差异基因的显著性与平均表达量对其进行了排序,从中选取了6个前20的上调基因进行验证,RT-PCR结果显示,与正常组相比,AGMAT、CCL25、FABP1、CDX1、SPINK4和MUC2表达水平显著上调(P<0.05)。 结论 AGMAT、CCL25、FABP1、SPINK4、CDX1和MUC2可能是诊断肠上皮化生的潜在生物学标志物,参与了IM的发生、发展,对疾病的预测及诊断有一定的价值。
裴蓓, 张艺, 魏思源, 梅语, 宋标, 董港, 温子昂, 李学军. 基于转录组学测序及生物信息学方法鉴定肠上皮化生的潜在致病基因[J]. 南方医科大学学报, 2024, 44(5): 941-949.
Bei PEI, Yi ZHANG, Siyuan WEI, Yu MEI, Biao SONG, Gang DONG, Ziang WEN, Xuejun LI. Identification of potential pathogenic genes of intestinal metaplasia based on transcriptomic sequencing and bioinformatics analysis[J]. Journal of Southern Medical University, 2024, 44(5): 941-949.
Name | Forward primer | Reverse primer |
---|---|---|
AGMAT | 5′-CTCACTCCTAGTCAGGCTC-3′ | 5′-TGAAACTTCGACAAGATCACAG-3′ |
CCL25 | 5′-CACCCAAGGTGTCTTTGAG-3′ | 5′-CTGGATCCGGTAAGTCCAG-3′ |
FABP1 | 5′-CATGAAGGCAATCGGTCTG-3′ | 5′-CCATTCTGCACGATTTCCG-3′ |
SPINK4 | 5′-TCAAGAATGCCCATCTGTG-3′ | 5′-ATATGTGAGCCCATCAGTG-3′ |
CDX1 | 5′-TCGGACCAAGGACAAGTACC-3′ | 5′-AGATCTTCACCTGCCGTTCA-3′ |
MUC2 | 5′-GCTGTCCCTTCTACTGGTGT-3′ | 5′-GTTGAGCAGGGTGTTGTTGT-3′ |
表1 关键基因的PCR引物序列
Tab.1 PCR primer sequences of the target genes
Name | Forward primer | Reverse primer |
---|---|---|
AGMAT | 5′-CTCACTCCTAGTCAGGCTC-3′ | 5′-TGAAACTTCGACAAGATCACAG-3′ |
CCL25 | 5′-CACCCAAGGTGTCTTTGAG-3′ | 5′-CTGGATCCGGTAAGTCCAG-3′ |
FABP1 | 5′-CATGAAGGCAATCGGTCTG-3′ | 5′-CCATTCTGCACGATTTCCG-3′ |
SPINK4 | 5′-TCAAGAATGCCCATCTGTG-3′ | 5′-ATATGTGAGCCCATCAGTG-3′ |
CDX1 | 5′-TCGGACCAAGGACAAGTACC-3′ | 5′-AGATCTTCACCTGCCGTTCA-3′ |
MUC2 | 5′-GCTGTCCCTTCTACTGGTGT-3′ | 5′-GTTGAGCAGGGTGTTGTTGT-3′ |
Indexes | Control group | IM group | P |
---|---|---|---|
Age (year) | 56.76±10.64 | 60.62±9.02 | 0.2124 |
Gender | 0.7579 | ||
Male | 10 | 12 | |
Female | 11 | 9 | |
Smoking history | 0.6965 | ||
Yes | 3 | 5 | |
No | 18 | 16 | |
Drinking history | 0.4841 | ||
Yes | 4 | 7 | |
No | 17 | 14 | |
Diet | 0.6060 | ||
Irregular | 1 | 3 | |
Regular | 20 | 18 | |
Diabetes | 0.9999 | ||
Yes | 0 | 1 | |
No | 21 | 20 | |
Hypertension | 0.6965 | ||
Yes | 3 | 5 | |
No | 18 | 16 | |
Hyperlipidemia | 0.7186 | ||
Yes | 4 | 6 | |
No | 17 | 15 | |
Family history of tumors | 0.6060 | ||
Yes | 1 | 3 | |
No | 20 | 18 | |
H. pylori infection | 0.9999 | ||
Yes | 0 | 0 | |
No | 21 | 21 |
表2 所有受试者的临床数据分析
Tab.2 Demographic and clinical characteristics of the 21 patients with intestinal metaplasia (IM) and the control subjects
Indexes | Control group | IM group | P |
---|---|---|---|
Age (year) | 56.76±10.64 | 60.62±9.02 | 0.2124 |
Gender | 0.7579 | ||
Male | 10 | 12 | |
Female | 11 | 9 | |
Smoking history | 0.6965 | ||
Yes | 3 | 5 | |
No | 18 | 16 | |
Drinking history | 0.4841 | ||
Yes | 4 | 7 | |
No | 17 | 14 | |
Diet | 0.6060 | ||
Irregular | 1 | 3 | |
Regular | 20 | 18 | |
Diabetes | 0.9999 | ||
Yes | 0 | 1 | |
No | 21 | 20 | |
Hypertension | 0.6965 | ||
Yes | 3 | 5 | |
No | 18 | 16 | |
Hyperlipidemia | 0.7186 | ||
Yes | 4 | 6 | |
No | 17 | 15 | |
Family history of tumors | 0.6060 | ||
Yes | 1 | 3 | |
No | 20 | 18 | |
H. pylori infection | 0.9999 | ||
Yes | 0 | 0 | |
No | 21 | 21 |
Name | Description | P |
---|---|---|
AGMAT | Agmatinase | 3.51×10-13 |
CCL25 | C-C motif chemokine ligand 25 | 8.86×10-13 |
FABP1 | Fatty acid binding protein 1 | 6.22×10-11 |
MUC2 | Mucin 2 | 1.95×10-10 |
SPINK4 | Serine peptidase inhibitor Kazal type 4 | 1.04×10-9 |
ANXA13 | Annexin A13 | 1.24×10-9 |
GIP | Gastric inhibitory polypeptide | 2.01×10-9 |
KCP | Kielin cysteine rich BMP regulator | 2.48×10-9 |
DEFA5 | Defensin alpha 5 | 2.55×10-9 |
ZG16 | Zymogen granule protein 16 | 4.38×10-9 |
CDX1 | Caudal type homeobox 1 | 9.33×10-9 |
RAB3B | RAB3B, member RAS oncogene family | 1.35×10-8 |
PTAFR | Platelet activating factor receptor | 2.37×10-8 |
RBP2 | Retinol binding protein 2 | 4.19×10-8 |
OLFM4 | Olfactomedin 4 | 4.19×10-8 |
ALPI | Alkaline phosphatase, intestinal | 6.04×10-8 |
MOCOS | Molybdenum cofactor sulfurase | 8.81×10-8 |
SLC6A20 | Solute carrier family 6 member 20 | 1.18×10-7 |
HOXB9 | Homeobox B9 | 2.88×10-7 |
CPS1 | Carbamoyl-phosphate synthase 1 | 3.00×10-7 |
表3 前20上调差异基因
Tab.3 Top 20 upregulated genes in intestinal metaplasia
Name | Description | P |
---|---|---|
AGMAT | Agmatinase | 3.51×10-13 |
CCL25 | C-C motif chemokine ligand 25 | 8.86×10-13 |
FABP1 | Fatty acid binding protein 1 | 6.22×10-11 |
MUC2 | Mucin 2 | 1.95×10-10 |
SPINK4 | Serine peptidase inhibitor Kazal type 4 | 1.04×10-9 |
ANXA13 | Annexin A13 | 1.24×10-9 |
GIP | Gastric inhibitory polypeptide | 2.01×10-9 |
KCP | Kielin cysteine rich BMP regulator | 2.48×10-9 |
DEFA5 | Defensin alpha 5 | 2.55×10-9 |
ZG16 | Zymogen granule protein 16 | 4.38×10-9 |
CDX1 | Caudal type homeobox 1 | 9.33×10-9 |
RAB3B | RAB3B, member RAS oncogene family | 1.35×10-8 |
PTAFR | Platelet activating factor receptor | 2.37×10-8 |
RBP2 | Retinol binding protein 2 | 4.19×10-8 |
OLFM4 | Olfactomedin 4 | 4.19×10-8 |
ALPI | Alkaline phosphatase, intestinal | 6.04×10-8 |
MOCOS | Molybdenum cofactor sulfurase | 8.81×10-8 |
SLC6A20 | Solute carrier family 6 member 20 | 1.18×10-7 |
HOXB9 | Homeobox B9 | 2.88×10-7 |
CPS1 | Carbamoyl-phosphate synthase 1 | 3.00×10-7 |
Name | Description | P |
---|---|---|
CARNS1 | Carnosine synthase 1 | 2.38×10-13 |
SH3GL2 | SH3 domain containing GRB2 like 2, endophilin A1FT | 3.08×10-13 |
RGMB | Repulsive guidance molecule BMP co-receptor bFT | 2.28×10-10 |
ZNF334 | Zinc finger protein 334 | 8.71×10-10 |
WIPF3 | WAS/WASL interacting protein family member 3FT | 4.81×10-9 |
PM20D1 | Peptidase M20 domain containing 1 | 5.08×10-9 |
KLHDC8A | Kelch domain containing 8A | 1.34×10-8 |
RGS7 | Regulator of G protein signaling 7 | 1.50×10-8 |
RGN | Regucalcin | 2.75×10-8 |
RPS6KA6 | Ribosomal protein S6 kinase A6 | 5.64×10-8 |
NCMAP | Non-compact myelin associated protein | 5.99×10-8 |
EDARADD | EDAR associated death domain | 7.13×10-8 |
GPC3 | Glypican 3 | 7.53×10-8 |
TMEM151A | Transmembrane protein 151A | 1.07×10-7 |
PER3 | Period circadian regulator 3 | 1.20×10-7 |
ZNF677 | Zinc finger protein 677 | 1.55×10-7 |
RNF217 | Ring finger protein 217 | 1.75×10-7 |
PWWP3B | PWWP domain containing 3B | 1.79×10-7 |
ZFP28 | ZFP28 zinc finger protein | 1.91×10-7 |
CYB5R1 | Cytochrome b5 reductase 1 | 2.74×10-7 |
表4 前20下调差异基因
Tab.4 Top 20 downregulated genes in intestinal metaplasia
Name | Description | P |
---|---|---|
CARNS1 | Carnosine synthase 1 | 2.38×10-13 |
SH3GL2 | SH3 domain containing GRB2 like 2, endophilin A1FT | 3.08×10-13 |
RGMB | Repulsive guidance molecule BMP co-receptor bFT | 2.28×10-10 |
ZNF334 | Zinc finger protein 334 | 8.71×10-10 |
WIPF3 | WAS/WASL interacting protein family member 3FT | 4.81×10-9 |
PM20D1 | Peptidase M20 domain containing 1 | 5.08×10-9 |
KLHDC8A | Kelch domain containing 8A | 1.34×10-8 |
RGS7 | Regulator of G protein signaling 7 | 1.50×10-8 |
RGN | Regucalcin | 2.75×10-8 |
RPS6KA6 | Ribosomal protein S6 kinase A6 | 5.64×10-8 |
NCMAP | Non-compact myelin associated protein | 5.99×10-8 |
EDARADD | EDAR associated death domain | 7.13×10-8 |
GPC3 | Glypican 3 | 7.53×10-8 |
TMEM151A | Transmembrane protein 151A | 1.07×10-7 |
PER3 | Period circadian regulator 3 | 1.20×10-7 |
ZNF677 | Zinc finger protein 677 | 1.55×10-7 |
RNF217 | Ring finger protein 217 | 1.75×10-7 |
PWWP3B | PWWP domain containing 3B | 1.79×10-7 |
ZFP28 | ZFP28 zinc finger protein | 1.91×10-7 |
CYB5R1 | Cytochrome b5 reductase 1 | 2.74×10-7 |
图1 IM相关差异基因的筛选和分析
Fig.1 Screening and analysis of the differentially expressed genes in intestinal metaplasia. A: Volcano plot of the differentially expressed genes. B: MA volcano plot of the differentially expressed genes. C: Histogram of the number of the differentially expressed genes. D: Venn diagram of the differentially expressed genes in transcriptomics sequencing group and the bioinformatic analysis group. E: Heatmap of the distribution of the differentially expressed genes in gastric tissues between the experimental and control groups. F: Genomic circle plot of the differentially expressed genes.
图5 关键基因的mRNA表达水平
Fig.5 Results of qRT-PCR for detecting mRNA expressions of AGMAT, CCL25, FABP1, SPINK4, MUC2 and CDX1 (A-F, respectively) in the gastric tissues of patients with intestinal metaplasia (IM) and the control subjects. *P<0.05, **P<0.01, ***P<0.001.
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