循环肿瘤细胞FCGBP和BIGH3作为结直肠癌潜在生物标志物的可行性研究

葛祖荫; 宋坤; 林云霄; 钟烨凌; 郝敬铎

doi:10.19401/j.cnki.1007-3639.2024.08.004

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循环肿瘤细胞FCGBP和BIGH3作为结直肠癌潜在生物标志物的可行性研究

论著 | 更新时间：2025-12-31

- 循环肿瘤细胞FCGBP和BIGH3作为结直肠癌潜在生物标志物的可行性研究
- The feasibility study of FCGBP and BIGH3 in circulating tumor cells as potential markers for colorectal cancer
- 中国癌症杂志 2024年34卷第8期页码：745-752
- 作者机构：
  
  镇海区人民医院普外二科，浙江宁波 315200
- 作者简介：
  
  [ "葛祖荫（ORCID: 0009-0008-9977-6429），副主任医师，镇海区人民医院普外二科科主任。" ]
  郝敬铎（ORCID:0009-0000-4463-8602），主任医师，镇海区人民医院党委书记。
- 基金信息：
  
  浙江省医药卫生科技计划项目(2020KY894);镇海区科技局公益类科技项目(2019S001)
- DOI：10.19401/j.cnki.1007-3639.2024.08.004
  中图分类号： R735.3+4
- 收稿：2024-03-09，
  
  修回：2024-06-18，
  
  纸质出版：2024-08-30
- 稿件说明：
移动端阅览
葛祖荫, 宋坤, 林云霄, 等. 循环肿瘤细胞FCGBP和BIGH3作为结直肠癌潜在生物标志物的可行性研究[J]. 中国癌症杂志, 2024,34(8):745-752.

Zuyin GE, Kun SONG, Yunxiao LIN, et al. The feasibility study of FCGBP and BIGH3 in circulating tumor cells as potential markers for colorectal cancer[J]. China Oncology, 2024, 34(8): 745-752.
葛祖荫, 宋坤, 林云霄, 等. 循环肿瘤细胞FCGBP和BIGH3作为结直肠癌潜在生物标志物的可行性研究[J]. 中国癌症杂志, 2024,34(8):745-752. DOI： 10.19401/j.cnki.1007-3639.2024.08.004.

Zuyin GE, Kun SONG, Yunxiao LIN, et al. The feasibility study of FCGBP and BIGH3 in circulating tumor cells as potential markers for colorectal cancer[J]. China Oncology, 2024, 34(8): 745-752. DOI： 10.19401/j.cnki.1007-3639.2024.08.004.

摘要

背景与目的：

结直肠癌（colorectal cancer，CRC）是全球常见的恶性肿瘤之一，且晚期患者的预后较差，寻找新的CRC潜在生物标志物的需求日益增加。循环肿瘤细胞（circulating tumor cell，CTC）从原发肿瘤脱落并进入循环系统，可在血液中被检测到，被认为是CRC的重要生物标志物。本研究旨在探讨CRC中的FCGBP和BIGH3是否可作为结直肠癌的潜在生物标志物。

方法：

本研究从基因表达综合数据库（Gene Expression Omnibus，GEO）获取了3个有CTC的CRC数据集，分别为GSE74369、GSE117606和GS

E164191。通过生物信息学分析在CTC和正常样本之间筛选出差异表达基因。其中一个包含临床信息的数据集用于WGCNA分析，并鉴定了两个关键基因模块，共包含1 148个基因。然后对这些模块中的基因进行了功能富集分析。使用Venn图、PPI调控网络构建分析和筛选候选基因。最后，使用癌症基因组图谱（The Cancer Genome Atlas，TCGA）和基因型-组织表达数据库（Genotype-Tissue Expression，GTEx）数据进行生存分析，并鉴定出与CRC相关的关键基因。在结直肠癌组织中通过实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction，RTFQ-PCR）验证

BIGH

3基因表达，并通过克隆形成、划痕实验以及transwell实验等功能实验在HCT116和SW620细胞系中验证

BIGH

3基因与结直肠癌的关系。

结果：

通过GEO中CRC数据集分析，共筛选出了2 214个差异基因，通过WGCNA分析和PPI网络构建鉴定出4个与CRC相关的CTC基因。通过GEPIA数据库进行生存分析发现， FCGBP及BIGH3与总生存期及无疾病生存期具有相关性。进一步实验表明，

BIGH

3基因在30对配对的结直肠癌样本中呈高表达，在HCT116和SW620细胞系中敲低BIGH3的表达能够减慢细胞增殖和迁移的速度，并降低侵袭性，而上调BIGH3的表达则会增加其侵袭性或提高迁移率。

结论：

本研究结果表明，FCGBP及BIGH3与TNM分期呈正相关，这暗示它们在CRC发展中的重要作用，具有较好的预后价值，其可以作为潜在的CRC生物标志物，并可能作为潜在的治疗靶点。同时，我们的实验数据也揭示了BIGH3在结直肠癌中的重要角色，它可能影响结直肠癌的生物学行为。

Abstract

Background and purpose:

Colorectal cancer (CRC) is globally recognized as one of the most prevalent malignant tumors. Advanced CRC is marked by a relatively poor prognosis for patients

signifying an urgent need to identify novel potential biomarkers for CRC. A particular focus has been given to circulating tumor cells (CTC)

which are cells that have detached from the primary tumor mass and subsequently entered the circulatory system. These cells can be detected within the blood and are currently considered significant potential biomarkers for CRC. This study aimed to investigate if FCGBP and BIGH3 in CRC could be potential markers for colorectal cancer.

Methods:

This study obtained 3 CRC datasets (GSE74369

GSE117606

and GSE164191) with CTC from the GEO database. Bioinformatics analysis was conducted to screen differentially expressed genes between CTC and normal samples. One dataset that includes clinical information was used for WGCNA analysis

and two key gene modules were identified

containing 1 148 genes in total. Then

functional enrichment analys

is was carried out for these genes in the modules. Venn diagrams

PPI network construction analysis

and candidate gene screening were employed. Finally

survival analysis was performed using TCGA and GTEx data in the GEPIAS database

and key genes associated with CRC were identified. The expression of

BIGH

3 gene was validated in colorectal cancer tissues by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR)

and its association with colorectal cancer was verified through clonogenic

scratch

and transwell assays in HCT116 and SW620 cell lines.

Results:

Through the analysis of CRC datasets from GEO

we screened a total of 2 214 differential genes. With the help of WGCNA analysis and PPI network construction

4 CTC-related genes associated with CRC were identified. Survival analysis from the GEPIA database revealed that FCGBP and BIGH3 are associated with overall survival and disease-free survival. Further experiments indicated that

BIGH

3 gene is overexpressed in 30 matched colorectal cancer samples. The downregulation of BIGH3 expression could slow down cell proliferation and migration rates

as well as decrease invasiveness in HCT116 and SW620 cell lines. In contrast

upregulation of BIGH3 expression could increase its invasiveness or accelerate migration rate.

Conclusion:

FCGBP and BIGH3 are positively correlated with TNM staging

indicating their pivotal roles in CRC progression. They bear good prognostic value and may serve as potential biological markers for CRC clinically

and could provide potential therapeutic targets. Moreover

our experimental data revealed the crucial role of BIGH3 in colorectal cancer

suggesting it may influence the biological behavior of this disease.

关键词

Keywords

references

BRAY F , LAVERSANNE M , SUNG H , et al . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J ] . CA Cancer J Clin , 2024 , 74 ( 3 ): 229 - 263 .

MASUISHI T , TANIGUCHI H , HAMAUCHI S , et al . Regorafenib versus trifluridine/tipiracil for refractory metastatic colorectal cancer: a retrospective comparison [J ] . Clin Colorectal Cancer , 2017 , 16 ( 2 ): e15-e22.

ZHOU L , WANG J Z , WANG J T , et al . Correlation analysis of MR/CT on colorectal cancer lymph node metastasis characteristics and prognosis [J ] . Eur Rev Med Pharmacol Sci , 2017 , 21 ( 6 ): 1219 - 1225 .

ZHANG J Y , ZHU Z , MIAO Z F , et al . The clinical significance and mechanisms of REG4 in human cancers [J ] . Front Oncol , 2020 , 10 : 559230 .

DOLATKHAH R , DASTGIRI S , EFTEKHAR SADAT A T , et al . Impact of RAS/RAF mutations on clinical and prognostic outcomes in metastatic colorectal cancer [J ] . Bioimpacts , 2021 , 11 ( 1 ): 5 - 14 .

SHEN M Y , ZHANG Z Y , WANG P . GLI3 promotes invasion and predicts poor prognosis in colorectal cancer [J ] . Biomed Res Int , 2021 , 2021 : 8889986 .

YE D X , WANG S S , HUANG Y , et al . USP43 directly regulates ZEB1 protein, mediating proliferation and metastasis of colorectal cancer [J ] . J Cancer , 2021 , 12 ( 2 ): 404 - 416 .

WENG X Y , CHEN W , HU W X , et al . PTPRB promotes metastasis of colorectal carcinoma via inducing epithelial-mesenchymal transition [J ] . Cell Death Dis , 2019 , 10 ( 5 ): 352.

FERREIRA M M , RAMANI V C , JEFFREY S S . Circulating tumor cell technologies [J ] . Mol Oncol , 2016 , 10 ( 3 ): 374 - 394 . DOI: 10.1016/j.molonc.2016.01.007 http://doi.org/10.1016/j.molonc.2016.01.007

BORK U , RAHBARI N N , SCHÖLCH S , et al . Circulating tumour cells and outcome in non-metastatic colorectal cancer: a prospective study [J ] . Br J Cancer , 2015 , 112 ( 8 ): 1306 - 1313 .

COHEN S J , PUNT C J A , IANNOTTI N , et al . Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer [J ] . J Clin Oncol , 2008 , 26 ( 19 ): 3213 - 3221 . DOI: 10.1200/JCO.2007.15.8923 http://doi.org/10.1200/JCO.2007.15.8923

HUANG X Z , GAO P , SONG Y X , et al . Relationship between circulating tumor cells and tumor response in colorectal cancer patients treated with chemotherapy: a meta-analysis [J ] . BMC Cancer , 2014 , 14 : 976 . DOI: 10.1186/1471-2407-14-976 http://doi.org/10.1186/1471-2407-14-976

RITCHIE M E , PHIPSON B , WU D , et al . Limma powers differential expression analyses for RNA-sequencing and microarray studies [J ] . Nucleic Acids Res , 2015 , 43 ( 7 ): e47.

LANGFELDER P , HORVATH S . WGCNA: an R package for weighted correlation network analysis [J ] . BMC Bioinformatics , 2008 , 9 : 559 . DOI: 10.1186/1471-2105-9-559 http://doi.org/10.1186/1471-2105-9-559

YU G C , WANG L G , HAN Y Y , et al . clusterProfiler: an R package for comparing biological themes among gene clusters [J ] . OMICS , 2012 , 16 ( 5 ): 284 - 287 . DOI: 10.1089/omi.2011.0118 http://doi.org/10.1089/omi.2011.0118

SZKLARCZYK D , GABLE A L , LYON D , et al . STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets [J ] . Nucleic Acids Res , 2019 , 47 ( D1 ): D607-D613.

TANG Z F , LI C W , KANG B X , et al . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses [J ] . Nucleic Acids Res , 2017 , 45 ( W1 ): W98-W102.

QUIROZ-REYES A G , ISLAS J F , DELGADO-GONZALEZ P , et al . Therapeutic approaches for metastases from colorectal cancer and pancreatic ductal carcinoma [J ] . Pharmaceutics , 2021 , 13 ( 1 ): 103.

MIYAMOTO D T , LEE R J , KALINICH M , et al . An RNA-based digital circulating tumor cell signature is predictive of drug response and early dissemination in prostate cancer [J ] . Cancer Discov , 2018 , 8 ( 3 ): 288 - 303 . DOI: 10.1158/2159-8290.CD-16-1406 http://doi.org/10.1158/2159-8290.CD-16-1406

ZHU L , HISSA B , GYŐRFFY B , et al . Characterization of stem-like circulating tumor cells in pancreatic cancer [J ] . Diagnostics , 2020 , 10 ( 5 ): 305.

PENG Y R , XU C X , WEN J , et al . Fatty acid metabolism-related lncRNAs are potential biomarkers for predicting the overall survival of patients with colorectal cancer [J ] . Front Oncol , 2021 , 11 : 704038 .

GILKES D M , SEMENZA G L , WIRTZ D . Hypoxia and the extracellular matrix: drivers of tumour metastasis [J ] . Nat Rev Cancer , 2014 , 14 ( 6 ): 430 - 439 . DOI: 10.1038/nrc3726 http://doi.org/10.1038/nrc3726

HANLEY C J , NOBLE F , WARD M , et al . A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers [J ] . Oncotarget , 2016 , 7 ( 5 ): 6159 - 6174 . DOI: 10.18632/oncotarget.6740 http://doi.org/10.18632/oncotarget.6740

RĂCHIERIU C , ENIU D T , MOIŞ E , et al . Lipidomic signatures for colorectal cancer diagnosis and progression using UPLC-QTOF-ESI+MS [J ] . Biomolecules , 2021 , 11 ( 3 ): 417.

CALAF G M , ECHIBURÚ-CHAU C , ZHAO Y L , et al . BigH3 protein expression as a marker for breast cancer [J ] . Int J Mol Med , 2008 , 21 ( 5 ): 561 - 568 .

ZHAO Y L , EL-GABRY M , HEI T K . Loss of Betaig-h3 protein is frequent in primary lung carcinoma and related to tumorigenic phenotype in lung cancer cells [J ] . Mol Carcinog , 2006 , 45 ( 2 ): 84 - 92 .

PAN T H , LIN S C , YU K J , et al . BIGH3 promotes osteolytic lesions in renal cell carcinoma bone metastasis by inhibiting osteoblast differentiation [J ] . Neoplasia , 2018 , 20 ( 1 ): 32 - 43 . DOI: S1476-5586(17)30393-7 http://doi.org/S1476-5586(17)30393-7

CHIAVARINA B , COSTANZA B , RONCA R , et al . Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis [J ] . Theranostics , 2021 , 11 ( 4 ): 1626 - 1640 . DOI: 10.7150/thno.51507 http://doi.org/10.7150/thno.51507

PAN X , MA X X . A novel six-gene signature for prognosis prediction in ovarian cancer [J ] . Front Genet , 2020 , 11 : 1006 . DOI: 10.3389/fgene.2020.01006 http://doi.org/10.3389/fgene.2020.01006

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