Serpine1 MRNA Confers Mesenchymal Characteristics to the Cell and Promotes CD8+ T Cells Exclusion from Colon Adenocarcinomas

Overview

Journal Cell Death Discov

Date 2024 Mar 6

PMID 38448406

Authors

Salvador Polo-Generelo

Cristina Rodriguez-Mateo

Belen Torres

Jose Pintor-Tortolero

Jose A Guerrero-Martinez

Julian Konig

Jesus Vazquez

Elena Bonzon-Kulichenco

Javier Padillo-Ruiz

Fernando De La Portilla

Jose C Reyes

Jose A Pintor-Toro

Affiliations

Soon will be listed here.

Abstract

Serine protease inhibitor clade E member 1 (SERPINE1) inhibits extracellular matrix proteolysis and cell detachment. However, SERPINE1 expression also promotes tumor progression and plays a crucial role in metastasis. Here, we solve this apparent paradox and report that Serpine1 mRNA per se, independent of its protein-coding function, confers mesenchymal properties to the cell, promoting migration, invasiveness, and resistance to anoikis and increasing glycolytic activity by sequestering miRNAs. Expression of Serpine1 mRNA upregulates the expression of the TRA2B splicing factor without affecting its mRNA levels. Through transcriptional profiling, we found that Serpine1 mRNA expression downregulates through TRA2B the expression of genes involved in the immune response. Analysis of human colon tumor samples showed an inverse correlation between SERPINE1 mRNA expression and CD8+ T cell infiltration, unveiling the potential value of SERPINE1 mRNA as a promising therapeutic target for colon tumors.

Citing Articles

Characterization and Experimental Use of Multiple Myeloma Bone Marrow Endothelial Cells and Progenitors.

Garbicz F, Kaszkowiak M, Dudkiewicz-Garbicz J, Dorfman D, Ostrowska J, Barankiewicz J Int J Mol Sci. 2024; 25(22).

PMID: 39596117 PMC: 11594118. DOI: 10.3390/ijms252212047.

Tang M, Rong Y, Li X, Pan H, Tao P, Wu Z BMC Cancer. 2024; 24(1):1163.

PMID: 39300389 PMC: 11411761. DOI: 10.1186/s12885-024-12830-5.

Culture Conditions Differentially Regulate the Inflammatory Niche and Cellular Phenotype of Tracheo-Bronchial Basal Stem Cells.

Murthy S, Seabold D, Gautam L, Caceres A, Sease R, Calvert B bioRxiv. 2024; .

PMID: 39282256 PMC: 11398510. DOI: 10.1101/2024.09.04.611264.

Bioinformatic Analyses and Integrated Machine Learning to Predict prognosis and therapeutic response Based on E3 Ligase-Related Genes in colon cancer.

Liang L, Liang X, Yu X, Xiang W J Cancer. 2024; 15(16):5376-5395.

PMID: 39247594 PMC: 11375543. DOI: 10.7150/jca.98723.

References

Buccitelli C, Selbach M . mRNAs, proteins and the emerging principles of gene expression control. Nat Rev Genet. 2020; 21(10):630-644. DOI: 10.1038/s41576-020-0258-4. View

Haberman N, Huppertz I, Attig J, Konig J, Wang Z, Hauer C . Insights into the design and interpretation of iCLIP experiments. Genome Biol. 2017; 18(1):7. PMC: 5240381. DOI: 10.1186/s13059-016-1130-x. View

Diepenbruck M, Tiede S, Saxena M, Ivanek R, Kalathur R, Luond F . miR-1199-5p and Zeb1 function in a double-negative feedback loop potentially coordinating EMT and tumour metastasis. Nat Commun. 2017; 8(1):1168. PMC: 5660124. DOI: 10.1038/s41467-017-01197-w. View

Izuhara Y, Yamaoka N, Kodama H, Dan T, Takizawa S, Hirayama N . A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates. J Cereb Blood Flow Metab. 2010; 30(5):904-12. PMC: 2949193. DOI: 10.1038/jcbfm.2009.272. View

Placencio V, DeClerck Y . Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing. Cancer Res. 2015; 75(15):2969-74. PMC: 4613764. DOI: 10.1158/0008-5472.CAN-15-0876. View

Hwang W, Adams S, Tahirovic E, Hagemann I, Coukos G . Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2011; 124(2):192-8. PMC: 3298445. DOI: 10.1016/j.ygyno.2011.09.039. View

Brummer A, Hausser J . MicroRNA binding sites in the coding region of mRNAs: extending the repertoire of post-transcriptional gene regulation. Bioessays. 2014; 36(6):617-26. DOI: 10.1002/bies.201300104. View

Tong H, Li K, Zhou M, Wu R, Yang H, Peng Z . Coculture of cancer cells with platelets increases their survival and metastasis by activating the TGFβ/Smad/PAI-1 and PI3K/AKT pathways. Int J Biol Sci. 2023; 19(13):4259-4277. PMC: 10496510. DOI: 10.7150/ijbs.85986. View

Cerami E, Gao J, Dogrusoz U, Gross B, Sumer S, Aksoy B . The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2(5):401-4. PMC: 3956037. DOI: 10.1158/2159-8290.CD-12-0095. View

10.

Krakau S, Richard H, Marsico A . PureCLIP: capturing target-specific protein-RNA interaction footprints from single-nucleotide CLIP-seq data. Genome Biol. 2017; 18(1):240. PMC: 5746957. DOI: 10.1186/s13059-017-1364-2. View

11.

Musha H, Ohtani H, Mizoi T, Kinouchi M, Nakayama T, Shiiba K . Selective infiltration of CCR5(+)CXCR3(+) T lymphocytes in human colorectal carcinoma. Int J Cancer. 2005; 116(6):949-56. DOI: 10.1002/ijc.21135. View

12.

Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z . Proteogenomic characterization of human colon and rectal cancer. Nature. 2014; 513(7518):382-7. PMC: 4249766. DOI: 10.1038/nature13438. View

13.

Wang B, Gu B, Zhang T, Li X, Wang N, Ma C . Good or bad: Paradox of plasminogen activator inhibitor 1 (PAI-1) in digestive system tumors. Cancer Lett. 2023; 559:216117. DOI: 10.1016/j.canlet.2023.216117. View

14.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

15.

Grant C, Bailey T, Noble W . FIMO: scanning for occurrences of a given motif. Bioinformatics. 2011; 27(7):1017-8. PMC: 3065696. DOI: 10.1093/bioinformatics/btr064. View

16.

Zhang L, Conejo-Garcia J, Katsaros D, Gimotty P, Massobrio M, Regnani G . Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177. View

17.

Best A, Dagliesh C, Ehrmann I, Kheirollahi-Kouhestani M, Tyson-Capper A, Elliott D . Expression of Tra2 β in Cancer Cells as a Potential Contributory Factor to Neoplasia and Metastasis. Int J Cell Biol. 2013; 2013:843781. PMC: 3723085. DOI: 10.1155/2013/843781. View

18.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C . Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795):1960-4. DOI: 10.1126/science.1129139. View

19.

Harlin H, Meng Y, Peterson A, Zha Y, Tretiakova M, Slingluff C . Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009; 69(7):3077-85. PMC: 3886718. DOI: 10.1158/0008-5472.CAN-08-2281. View

20.

Lorenzo C, Delgado P, Busse C, Sanz-Bravo A, Martos-Folgado I, Bonzon-Kulichenko E . ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies. Nature. 2020; 589(7841):287-292. DOI: 10.1038/s41586-020-2993-2. View