基于生物信息学分析抑制素在消化系统恶性肿瘤中的表达及预后价值

李晓凤; 刘禧禧; 宋子晴; 唐明政; 蔡辉; 张凌云

doi:10.16016/j.2097-0927.202306086

您当前的位置：

首页 >

文章列表页 >

基于生物信息学分析抑制素在消化系统恶性肿瘤中的表达及预后价值

基础医学 | 更新时间：2026-01-09

- 基于生物信息学分析抑制素在消化系统恶性肿瘤中的表达及预后价值
- Expression and prognostic value of prohibitin in gastrointestinal cancers based on bioinformatics
- 陆军军医大学学报 2024年46卷第16期页码：1838-1848
- 作者机构：
  
  1.730000 兰州，甘肃中医药大学第一临床医学院
  2.730000 兰州，甘肃省人民医院普外科
  3.730050 兰州，甘肃省中医院外科临床中心
- 作者简介：
  
  [张凌云，E-mail: Zhangly8848@126.comZHANG Lingyun, E-mail: Zhangly8848@126.com
- 基金信息：
  
  甘肃省自然科学基金(20JR5RA159);甘肃中医药大学2023年度研究生创新创业基金(32号)
- DOI：10.16016/j.2097-0927.202306086
  中图分类号： R341;R730.23;R735
- 收稿：2023-06-24，
  
  修回：2023-11-13，
  
  纸质出版：2024-08-30
- 稿件说明：
移动端阅览
李晓凤, 刘禧禧, 宋子晴, 等. 基于生物信息学分析抑制素在消化系统恶性肿瘤中的表达及预后价值[J]. 陆军军医大学学报, 2024,46(16):1838-1848.

Xiaofeng LI, Xixi LIU, Ziqing SONG, et al. Expression and prognostic value of prohibitin in gastrointestinal cancers based on bioinformatics[J]. Journal of Army Medical University, 2024, 46(16): 1838-1848.
李晓凤, 刘禧禧, 宋子晴, 等. 基于生物信息学分析抑制素在消化系统恶性肿瘤中的表达及预后价值[J]. 陆军军医大学学报, 2024,46(16):1838-1848. DOI： 10.16016/j.2097-0927.202306086.

Xiaofeng LI, Xixi LIU, Ziqing SONG, et al. Expression and prognostic value of prohibitin in gastrointestinal cancers based on bioinformatics[J]. Journal of Army Medical University, 2024, 46(16): 1838-1848. DOI： 10.16016/j.2097-0927.202306086.

摘要

目的

探索肿瘤组织中抑制素(prohibitin

PHB

)的表达情况

分析其对消化系统恶性肿瘤(digestive system malignant tumor

DT)患者预后的影响以及作用机制。

方法

① 使用癌

症基因组图谱(the Cancer Genome Atlas

TCGA)和基因型-组织表达(Genotype-Tissue Expression

GTEx)数据库比较肿瘤组织和正常组织中

PHB

的表达差异。②收集2023年10月甘肃省人民医院诊治的5对胃癌及癌旁组织和5对结肠癌及癌旁组织

RT-qPCR检测

PHB

mRNA表达水平。③采用RT-qPCR和Western blot检测正常胃黏膜细胞(GES-1)和胃癌细胞(AGS、MKN45和HGC27)、正常结肠细胞NCM-460和人结肠癌细胞株SW480中

PHB

的表达差异。④利用R语言分析

PHB

对DT患者预后、肿瘤微环境、肿瘤突变负荷和微卫星不稳定性的影响。⑤采用CIBERSORT算法分析肿瘤组织中

PHB

表达与肿瘤免疫细胞浸润之间的相关性。基因集富集分析(Gene Set Enrichment Analysis

GSEA)探讨

PHB

的生物学功能。⑥利用R语言分析

PHB

与药物敏感性的关系。

结果

①

PHB

在结肠癌、胆管癌、食管癌、肝癌、直肠癌和胃癌组织中均显著高表达(

0.01)。②RT-qPCR和Western blot检测结果显示

PHB

在胃癌和结肠癌组织和细胞中高表达(

0.01)。③

PHB

的差异表达与肝癌(

=0.002)预后不良相关。在胆管癌、胃癌、胰腺癌、肝癌和食管癌中

PHB

与肿瘤突变负荷和微卫星不稳定性呈正相关(

0.05)。④

PHB

的表达在结肠癌中与M2型巨噬细胞呈正相关(

=0.03);在胆管癌中与活化CD4

记忆T细胞呈正相关(

0.05);在食管癌中与活化肥大细胞呈正相关(

=0.03);在肝癌中与M0、M2型巨噬细胞和单核细胞呈正相关(

0.05);在直肠癌中与静息树突状细胞、嗜酸性粒细胞和活化CD4

记忆T细胞呈正相关(

0.05);在胃癌中与M0型巨噬细胞、活化肥大细胞、中性粒细胞、静息自然杀伤细胞、活化CD4

记忆T细胞和滤泡辅助性T细胞呈正相关(

0.05)。⑤

PHB

在Ⅰ类受体、PPAR和钙离子信号通路中主要富集(

0.05)。⑥

PHB

的表达与氨萘非特、普拉西诺特和阿比特龙等13种药物敏感性呈正相关(

0.05)。

结论

PHB

表达与DT中多种免疫细胞浸润及不良预后有关

其可能成为新型DT生物标志物及潜在的免疫调节靶点。

Abstract

Objective

To explore the expression of prohibitin (PHB) in tumor tissues and analyze its effect on the prognosis of patients with digestive system malignant tumor (DT) and its mechanism.

Methods

① The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database were used to compare the expression of PHB in tumor tissues and normal tissues.②Five pairs of gastric cancer and adjacent tissues and 5 pairs of colon cancer and adjacent tissues were collected

and RT-qPCR was used to verify the mRNA expression levels.③RT-qPCR and Western blotting were used to verify the differential expression of PHB in normal gastric mucosa cells (GES-1)

gastric cancer cells (AGS

MKN45 and HGC27)

normal colon cells NCM-460 and human colon cancer cell line SW480.④R language was used to analyze the effect of PHB on the prognosis

tumor microenvironment

tumor mutation burden and microsatellite instability of DT patients.⑤CIBERSORT algorithm was used to study the correlation between PHB expression in tumor tissues and tumor immune cell infiltration.Gene Set Enrichment Analysis (GSEA) was used to explore the biological function of PHB.⑥R language was used to analyze the relationship between PHB and drug sensitivity.

Results

① PHB was highly expressed in colon cancer

cholangiocarcinoma

esophageal cancer

liver cancer

rectal cancer and gastric cancer (

0.01).②RT-qPCR and Western blotting showed that PHB was highly expressed in the tissues and cell lines of gastric cancer (

0.01) and colon cancer (

0.01).③The differential expression of PHB was associated with poor prognosis of hepatocellular carcinoma (

=0.002).In cholangiocarcinoma

gastric cancer

pancreatic cancer

liver cancer and esophageal cancer

PHB was positively correlated with tumor mutation burden and microsatellite instability (

0.05).④PHB was positively correlated with M2 macrophages in colon cancer (

=0.03).In cholangiocarcinoma

it was positively correlated with activated CD4

memory T cells (

0.05).In esophageal carcinoma

it was positively correlated with activated hypertrophy (

=0.03).It was positively correlated with M0 and M2 macrophages and monocytes in hepatocellu

lar carcinoma (

0.05).It was positively correlated with resting dendritic cells

eosinophils and activated CD4

memory T cells in rectal cancer (

0.05).It was positively correlated with M0 macrophages

activated mast cells

neutrophils

resting natural killer cells

activated CD4

memory T cells and follicular helper T cells in gastric cancer (

0.05).⑤PHB was mainly enriched in class I receptors

PPAR and calcium signaling pathways (

0.05).⑥ The expression of PHB was positively correlated with the sensitivity of 13 drugs

including ammonafide

prasinolide and abiraterone (

0.05).

Conclusion

The expression of PHB is significantly related to the infiltration of various immune cells in DT and poor prognosis in DT patients

which may become a new biomarker and potential immunomodulatory target of DT.

关键词

Keywords

references

TANG J, CHEN J W, WANG Y Q, et al . The role of MiRNA-433 in malignant tumors of digestive tract as tumor suppressor[J ] . Cancer Rep (Hoboken), 2022, 5(9): e1694. DOI: 10.1002/cnr2.1694.

REITANO E, DE'ANGELIS N, GAVRⅡLIDIS P, et al . Oral bacterial microbiota in digestive cancer patients: a systematic review[J ] . Microorganisms, 2021, 9(12): 2585. DOI: 10.3390/microorganisms9122585.

WANG J T, MA X, SI H, et al . Role of long non-coding RNA H19 in therapy resistance of digestive system cancers[J ] . Mol Med, 2021, 27(1): 1. DOI: 10.1186/s10020-020-00255-2.

WHITE J J , LEDBETTER D H, EDDY R L Jr, et al . Assignment of the human prohibition gene (PHB) to chromosome 17 and identification of a DNA polymorphism[J ] . Genomics, 1991, 11(1): 228-230. DOI: 10.1016/0888-7543(91)90126-y.

MISHRA S, MURPHY L C, NYOMBA B L, et al . Prohibitin: a potential target for new therapeutics[J ] . Trends Mol Med, 2005, 11(4): 192-197. DOI: 10.1016/j.molmed.2005.02.004.

MISHRA S, ANDE S R, NYOMBA B L G. The role of prohibitin in cell signaling[J]. FEBS J, 2010, 277(19): 3937-3946. DOI: 10.1111/j.1742-4658.2010.07809.x.

SIMONS K, TOOMRE D. Lipid rafts and signal transduction[J]. Nat Rev Mol Cell Biol, 2000, 1(1): 31-39. DOI: 10.1038/35036052.

IJSSELSTEIJN R, JANSEN J G, DE WIND N. DNA mismatch repair-dependent DNA damage responses and cancer[J]. DNA Repair (Amst), 2020, 93: 102923. DOI: 10.1016/j.dnarep.2020.102923.

KANEHISA M, FURUMICHI M, SATO Y, et al . KEGG: integrating viruses and cellular organisms[J ] . Nucleic Acids Res, 2021, 49(D1): D545-D551. DOI: 10.1093/nar/gkaa970.

王润媛, 陈星材, 吴蔚, 等. 基于增强CT图像和Swin Transformer网络的食管癌T分期智能诊断模型的构建与评估[J]. 陆军军医大学学报, 2023, 45(16): 1770-1778. DOI:10.16016/j.2097-0927.202302021.

WANG R Y, CHEN X C, WU W, et al . Construction and evaluation of an intelligent diagnosis model for T staging of esophageal cancer based on contrast-enhanced CT images and Swin Transformer network[J ] . J Army Med Univ, 2023, 45(16): 1770-1778. DOI:10.16016/j.2097-0927.202302021.

郭丹, 李雅睿, 张旭, 等. FKBP10促进胃癌细胞增殖与转移的机制研究[J]. 陆军军医大学学报, 2023, 45(11): 1181-1188. DOI:10.16016/j.2097-0927.202206078.

GUO D, LI Y R, ZHANG X, et al . Mechanism of FKBP10 promoting the proliferation and metastasis of gastric cancer cells[J ] . J Army Med Univ, 2023, 45(11): 1181-1188. DOI:10.16016/j.2097-0927.202206078.

孙燕, 王灵巧, 张国伟, 等. ACSS2介导的上皮间质转化在乙醇促结直肠癌细胞迁移中的作用及机制[J]. 陆军军医大学学报, 2023, 45(17): 1806-1818. DOI:10.16016/j.2097-0927.202303141.

SUN Y, WANG L Q, ZHANG G W, et al . The role and mechanism of ACSS2-mediated epithelial-mesenchymal transition in ethanol-induced migration of colorectal cancer cells[J ] . J Army Med Univ, 2023, 45(17): 1806-1818. DOI:10.16016/j.2097-0927.202303141.

王松, 张炳兰, 张秉强. 靶向EPCAM的CAR-T细胞抗肝癌细胞的体外杀伤性研究[J]. 陆军军医大学学报, 2023, 45(18): 1947-1954. DOI: 10.16016/j.2097-0927.202205133.

WANG S, ZHANG B L, ZHANG B Q. Effects of CAR-T cells targeting EPCAM on liver cancer cells in vitro [J ] . J Army Med Univ, 2023, 45(18): 1947-1954. DOI: 10.16016/j.2097-0927.202205133.

张旭东, 刘浩昂, 王志浩, 等. Smad3通过p38/MAPK信号通路调控细胞自噬及凋亡促进胰腺癌进程[J]. 陆军军医大学学报, 2022, 44(19): 1968-1978. DOI:10.16016/j.2097-0927.202205059.

ZHANG X D, LIU H A, WANG Z H, et al . Smad3 promotes the progression of pancreatic cancer by regulating autophagy and apoptosis through p38/MAPK signaling pathway[J ] . J Army Med Univ, 2022, 44(19): 1968-1978. DOI:10.16016/j.2097-0927.202205059.

ANDE S R, NGUYEN K H, PADILLA-MEIER G P, et al . Expression of a mutant prohibitin from the aP2 gene promoter leads to obesity-linked tumor development in insulin resistance-dependent manner[J ] . Oncogene, 2016, 35(34): 4459-4470. DOI: 10.1038/onc.2015.501.

ROSTAMI-NEJAD M, REZAEI-TAVIRANI M, MANSOURI V, et al . Impact of proteomics investigations on gastric cancer treatment and diagnosis[J ] . Gastroenterol Hepatol Bed Bench, 2019, 12(Suppl1): S1-S7.

JIANG L, DONG P, ZHANG Z, et al . Akt phosphorylate s prohibitin 1 to mediate its mitochondrial localization and promote proliferation of bladder cancer cells[J ] . Cell Death Dis, 2015, 6(2): e1660. DOI: 10.1038/cddis.2015.40.

HAN Y Y, WU P, WANG Z, et al . Ubiquinol-cytochrome C reductase core protein Ⅱ promotes tumorigenesis by facilitating p53 degradation[J ] . EBioMedicine, 2019, 40: 92-105. DOI: 10.1016/j.ebiom.2019.01.002.

CHEN D B, CHEN F L, LU X R, et al . Identification of prohibitin as a potential biomarker for colorectal carcinoma based on proteomics technology[J ] . Int J Oncol, 2010, 37(2): 355-365. DOI: 10.3892/ijo_00000684.

BENTAYEB H, AITAMER M, PETIT B, et al . Prohibitin ( PHB ) expression is associated with aggressiveness in DLBCL and flavagline-mediated inhibition of cytoplasmic PHB functions induces anti-tumor effects[J ] . J Exp Clin Cancer Res, 2019, 38(1): 450. DOI: 10.1186/s13046-019-1440-4..

XU Z H, MIAO Z W, JIANG Q Z, et al . Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small-cell lung cancer cell survival in brain[J ] . FASEB J, 2019, 33(2): 1742-1757. DOI: 10.1096/fj.201800428R.

WANG W B, XU L, YANG Y, et al . A novel prognostic marker and immunogenic membrane antigen: prohibitin (PHB) in pancreatic cancer[J ] . Clin Transl Gastroenterol, 2018, 9(9): 178. DOI: 10.1038/s41424-018-0044-1.

MA W H, XU Z L, WANG Y T, et al . A positive feedback loop of SLP2 activates MAPK signaling pathway to promote gastric cancer progression[J ] . Theranostics, 2018, 8(20): 5744-5757. DOI: 10.7150/thno.28898.

KOSGODAGE U S, UYSAL-ONGANER P, MACLATCHY A, et al . Cannabidiol affects extracellular vesicle release, miR21 and miR126, and reduces prohibitin protein in glioblastoma multiforme cells[J ] . Transl Oncol, 2019, 12(3): 513-522. DOI: 10.1016/j.tranon.2018.12.004.

WANG H R, ZHOU Y J, OYANG L, et al . LPLUNC1 stabilises PHB 1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-κB activity in nasopharyngeal carcinoma[J ] . Oncogene, 2019, 38(25): 5062-5075. DOI: 10.1038/s41388-019-0778-6..

MA W H, CHEN Y H, XIONG W J, et al . STOML2 interacts with PHB through activating MAPK signaling pathway to promote colorectal Cancer proliferation[J ] . J Exp Clin Cancer Res, 2021, 40(1): 359. DOI: 10.1186/s13046-021-02116 -0..

WANG Y Q, CHEN H D, LIU Y X, et al . Treatment optimization for recurrent hepatoblastoma: retrospective study from a hepatoblastoma cohort in Southern China[J ] . Pediatr Surg Int, 2022, 38(7): 1031-1039. DOI: 10.1007/s00383-022-05126-x.

MA W, CHEN Y, XIONG W, et al . STOML2 interacts with PHB through activating MAPK signaling pathway to promote colorectal cancer proliferation[J ] . J Exp Clin Cancer Res, 2021, 40(1): 359. DOI:10.1186/s13046-021-02116-0.

VEENSTRA R G, FLYNN R, KREYMBORG K, et al . B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality[J ] . Blood, 2015, 125(21): 3335-3346. DOI: 10.1182/blood-2014-09-603357.

MACGREGOR H L, SAYAD A, ELIA A, et al . High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation[J ] . J Immunother Cancer, 2019, 7(1): 357. DOI: 10.1186/s40425-019-0816-5.

BOLTON-MAGGS P H B, GEORGE J N. Immune thrombocytopenia treatment[J]. N Engl J Med, 2021, 385(10): 948-950. DOI: 10.1056/NEJMe2110953.

XU Y X Z, ANDE S R, IKEOGU N M, et al . Prohibitin plays a role in the functional plasticity of macrophages[J ] . Mol Immunol, 2022, 144: 152-165. DOI: 10.1016/j.molimm.2022.02.014.

HUANG H, ZHANG S, LI Y, et al. Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance[J ] . Nat Commun, 2021, 12(1): 3720. DOI:10.1038/s41467-021-24108-6.

FANG C H, LIN Y T, LIANG C M, et al . A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3-PBX1 and β-catenin-ABCG2 signaling[J ] . J Biomed Sci, 2020, 27(1): 42. DOI:10.1186/s12929-020-00638-x..

NAJEM A, KRAYEM M, SABBAH S, et al . Targeting prohibitins to inhibit melanoma growth and overcome resistance to targeted therapies[J ] . Cells, 2023, 12(14). DOI:10.3390/cells12141855.

浏览量

168

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

基于普通转录组和单细胞转录组测序解析间质型胃癌复发风险相关的肿瘤细胞及微环境特征

基于中国人群的雌激素受体表达新分层（低/中/高）可更精准地预测HR⁺/HER2^-早期乳腺癌患者的预后

维莫德吉通过BRD9介导的PD-L1调控基底细胞癌微环境