Identification and Validation of Basement Membrane-associated Gene AGRN As Prognostic and Immune-associated Biomarkers in Colorectal Cancer Patients

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2024 Aug 26

PMID 39183444

Authors

Jianrong Li

Daofeng You

Linjie Hu

Yusi Yang

Sheng Gao

Wenqi Bai

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer (COCA) has a poor prognosis, with growing evidence implicating basement membranes (BMs) in cancer progression. Our goal was to investigate the role and predictive significance of BMs in COCA patients. We obtained BMs-related genes from cutting-edge research and used TCGA and GTEx databases for mRNA expression and patient information. Cox regression and LASSO regression were used for prognostic gene selection and risk model construction. We compared prognosis using Kaplan-Meier analysis and examined drug sensitivity differences. The CMAP dataset identified potential small molecule drugs. In vitro tests involved suppressing a crucial gene to observe its impact on tumour metastasis. We developed a 12 BMs-based approach, finding it to be an independent prognostic factor. Functional analysis showed BMs concentrated in cancer-associated pathways, correlating with immune cell infiltration and immune checkpoint activation. High-risk individuals exhibited increased drug sensitivity. AGRN levels were linked to decreased progression-free survival (p < 0.001). AGRN knockdown suppressed tumour growth and metastasis. Our study offers new perspectives on BMs in COCA, concluding that AGRN is a dependable biomarker for patient survival and prognosis.

References

Jury E, Eldridge J, Isenberg D, Kabouridis P . Agrin signalling contributes to cell activation and is overexpressed in T lymphocytes from lupus patients. J Immunol. 2007; 179(11):7975-83. PMC: 2596879. DOI: 10.4049/jimmunol.179.11.7975. View

Wang Z, Sun X, Wang Y, Miao Y . Agrin promotes the proliferation, invasion and migration of rectal cancer cells via the WNT signaling pathway to contribute to rectal cancer progression. J Recept Signal Transduct Res. 2020; 41(4):363-370. DOI: 10.1080/10799893.2020.1811325. View

Zhang H, Liang J, Lu T, Li M, Shan G, Bi G . AGRN promotes lung adenocarcinoma progression by activating Notch signaling pathway and acts as a therapeutic target. Pharmacol Res. 2023; 194:106819. DOI: 10.1016/j.phrs.2023.106819. View

Naba A, Clauser K, Whittaker C, Carr S, Tanabe K, Hynes R . Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver. BMC Cancer. 2014; 14:518. PMC: 4223627. DOI: 10.1186/1471-2407-14-518. View

Wang J, Liu D, Wang Q, Xie Y . Identification of Basement Membrane-Related Signatures in Gastric Cancer. Diagnostics (Basel). 2023; 13(11). PMC: 10252969. DOI: 10.3390/diagnostics13111844. View

Leclech C, Natale C, Barakat A . The basement membrane as a structured surface - role in vascular health and disease. J Cell Sci. 2020; 133(18). DOI: 10.1242/jcs.239889. View

Chen X, Xie D, Zhao Q, You Z . MicroRNAs and complex diseases: from experimental results to computational models. Brief Bioinform. 2017; 20(2):515-539. DOI: 10.1093/bib/bbx130. View

Yurchenco P . Basement membranes: cell scaffoldings and signaling platforms. Cold Spring Harb Perspect Biol. 2011; 3(2). PMC: 3039528. DOI: 10.1101/cshperspect.a004911. View

Han S, Zou H, Lee J, Han J, Kim H, Cheol J . miR-1307-3p Stimulates Breast Cancer Development and Progression by Targeting SMYD4. J Cancer. 2019; 10(2):441-448. PMC: 6360296. DOI: 10.7150/jca.30041. View

10.

Dekker E, Tanis P, Vleugels J, Kasi P, Wallace M . Colorectal cancer. Lancet. 2019; 394(10207):1467-1480. DOI: 10.1016/S0140-6736(19)32319-0. View

11.

Tian C, Ohlund D, Rickelt S, Lidstrom T, Huang Y, Hao L . Cancer Cell-Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma. Cancer Res. 2020; 80(7):1461-1474. PMC: 7127978. DOI: 10.1158/0008-5472.CAN-19-2578. View

12.

Neill T, Schaefer L, Iozzo R . Decoding the Matrix: Instructive Roles of Proteoglycan Receptors. Biochemistry. 2015; 54(30):4583-98. PMC: 4859759. DOI: 10.1021/acs.biochem.5b00653. View

13.

Randles M, Lausecker F, Kong Q, Suleiman H, Reid G, Kolatsi-Joannou M . Identification of an Altered Matrix Signature in Kidney Aging and Disease. J Am Soc Nephrol. 2021; 32(7):1713-1732. PMC: 8425653. DOI: 10.1681/ASN.2020101442. View

14.

Jayadev R, Sherwood D . Basement membranes. Curr Biol. 2017; 27(6):R207-R211. DOI: 10.1016/j.cub.2017.02.006. View

15.

Chen W, Yang Y, Zhang Z, An Q, Li N, Liu W . MiR-1307 promotes ovarian cancer cell chemoresistance by targeting the ING5 expression. J Ovarian Res. 2017; 10(1):1. PMC: 5234104. DOI: 10.1186/s13048-016-0301-4. View

16.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

17.

Pozzi A, Yurchenco P, Iozzo R . The nature and biology of basement membranes. Matrix Biol. 2017; 57-58:1-11. PMC: 5387862. DOI: 10.1016/j.matbio.2016.12.009. View

18.

Dang H, Ta H, Nguyen T, Anuraga G, Wang C, Lee K . Prospective role and immunotherapeutic targets of sideroflexin protein family in lung adenocarcinoma: evidence from bioinformatics validation. Funct Integr Genomics. 2022; 22(5):1057-1072. DOI: 10.1007/s10142-022-00883-3. View

19.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

20.

Jayadev R, Morais M, Ellingford J, Srinivasan S, Naylor R, Lawless C . A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations. Sci Adv. 2022; 8(20):eabn2265. PMC: 9116610. DOI: 10.1126/sciadv.abn2265. View