CYB5R1 Links Epithelial-mesenchymal Transition and Poor Prognosis in Colorectal Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Apr 28

PMID 27120783

Citations 12

Authors

Christine Woischke

Cristina Blaj

Eva Marina Schmidt

Sebastian Lamprecht

Jutta Engel

Heiko Hermeking

Thomas Kirchner

David Horst

Affiliations

Soon will be listed here.

Abstract

Colorectal cancers show significant tumor cell heterogeneity within the same core genetic background. Epithelial-mesenchymal transition (EMT) is an important functional aspect of this heterogeneity and hallmark of colorectal cancer progression. Here, we identify CYB5R1, an enzyme involved in oxidative stress protection and drug metabolism, as an indicator of EMT in colon cancer. We demonstrate high CYB5R1 expression in colorectal cancer cells undergoing EMT at the infiltrative tumor edge and reveal an extraordinarily strong association of CYB5R1 expression with two core EMT gene expression signatures in a large independent colon cancer data set from The Cancer Genome Atlas (TCGA). Furthermore, we demonstrate that CYB5R1 is required for an infiltrative tumor cell phenotype, and robustly linked with poor prognosis in colorectal cancer. Our findings have important implications for colon cancer cells undergoing EMT and may be exploited for diagnostic and therapeutic purposes.

Citing Articles

Analysis of the senescence-associated cell surfaceome reveals potential senotherapeutic targets.

Deng Y, Liu T, Scifo E, Li T, Xie K, Taschler B Aging Cell. 2024; 23(12):e14312.

PMID: 39228130 PMC: 11634743. DOI: 10.1111/acel.14312.

Regularized survival learning and cross-database analysis enabled identification of colorectal cancer prognosis-related immune genes.

Ai D, Wang M, Zhang Q, Cheng L, Wang Y, Liu X Front Genet. 2023; 14:1148470.

PMID: 36911403 PMC: 9995717. DOI: 10.3389/fgene.2023.1148470.

The Complex Dynamic of Phase I Drug Metabolism in the Early Stages of Doxorubicin Resistance in Breast Cancer Cells.

Barata I, Gomes B, Rodrigues A, Rueff J, Kranendonk M, Esteves F Genes (Basel). 2022; 13(11).

PMID: 36360213 PMC: 9689592. DOI: 10.3390/genes13111977.

Prognostic Factors Involved in the Epithelial-Mesenchymal Transition Process in Colorectal Cancer Have a Preponderant Role in Oxidative Stress: A Systematic Review and Meta-Analysis.

Parisi E, Sorolla A, Montal R, Gonzalez-Resina R, Novell A, Salud A Cancers (Basel). 2020; 12(11).

PMID: 33187205 PMC: 7697515. DOI: 10.3390/cancers12113330.

Prognostic Value of SLC4A4 and its Correlation with Immune Infiltration in Colon Adenocarcinoma.

Chen X, Chen J, Feng Y, Guan W Med Sci Monit. 2020; 26:e925016.

PMID: 32949121 PMC: 7526338. DOI: 10.12659/MSM.925016.

References

Fearon E, Hamilton S, Vogelstein B . Clonal analysis of human colorectal tumors. Science. 1987; 238(4824):193-7. DOI: 10.1126/science.2889267. View

Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T . Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005; 5(9):744-9. DOI: 10.1038/nrc1694. View

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

Bates R, Bellovin D, Brown C, Maynard E, Wu B, Kawakatsu H . Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest. 2005; 115(2):339-47. PMC: 544606. DOI: 10.1172/JCI23183. View

Xiao X, Zhao W, Tian F, Zhou X, Zhang J, Huang T . Cytochrome b5 reductase 2 is a novel candidate tumor suppressor gene frequently inactivated by promoter hypermethylation in human nasopharyngeal carcinoma. Tumour Biol. 2013; 35(4):3755-63. PMC: 3980038. DOI: 10.1007/s13277-013-1497-1. View

Gunderson L, Jessup J, Sargent D, Greene F, Stewart A . Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol. 2009; 28(2):264-71. PMC: 2815715. DOI: 10.1200/JCO.2009.24.0952. View

Spaderna S, Schmalhofer O, Hlubek F, Berx G, Eger A, Merkel S . A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology. 2006; 131(3):830-40. DOI: 10.1053/j.gastro.2006.06.016. View

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

Viera A, Garrett J . Understanding interobserver agreement: the kappa statistic. Fam Med. 2005; 37(5):360-3. View

10.

Sanchez-Tillo E, de Barrios O, Siles L, Cuatrecasas M, Castells A, Postigo A . β-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. Proc Natl Acad Sci U S A. 2011; 108(48):19204-9. PMC: 3228467. DOI: 10.1073/pnas.1108977108. View

11.

Hwang W, Yang M, Tsai M, Lan H, Su S, Chang S . SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology. 2011; 141(1):279-91, 291.e1-5. DOI: 10.1053/j.gastro.2011.04.008. View

12.

Taube J, Herschkowitz J, Komurov K, Zhou A, Gupta S, Yang J . Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A. 2010; 107(35):15449-54. PMC: 2932589. DOI: 10.1073/pnas.1004900107. View

13.

. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407):330-7. PMC: 3401966. DOI: 10.1038/nature11252. View

14.

Elahian F, Sepehrizadeh Z, Moghimi B, Mirzaei S . Human cytochrome b5 reductase: structure, function, and potential applications. Crit Rev Biotechnol. 2012; 34(2):134-43. DOI: 10.3109/07388551.2012.732031. View

15.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

16.

Anastassiou D, Rumjantseva V, Cheng W, Huang J, Canoll P, Yamashiro D . Human cancer cells express Slug-based epithelial-mesenchymal transition gene expression signature obtained in vivo. BMC Cancer. 2012; 11:529. PMC: 3268117. DOI: 10.1186/1471-2407-11-529. View

17.

Kirchner T, Brabletz T . Patterning and nuclear beta-catenin expression in the colonic adenoma-carcinoma sequence. Analogies with embryonic gastrulation. Am J Pathol. 2000; 157(4):1113-21. PMC: 1850184. DOI: 10.1016/s0002-9440(10)64626-3. View

18.

Toiyama Y, Yasuda H, Saigusa S, Tanaka K, Inoue Y, Goel A . Increased expression of Slug and Vimentin as novel predictive biomarkers for lymph node metastasis and poor prognosis in colorectal cancer. Carcinogenesis. 2013; 34(11):2548-57. DOI: 10.1093/carcin/bgt282. View

19.

Rokavec M, Oner M, Li H, Jackstadt R, Jiang L, Lodygin D . IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014; 124(4):1853-67. PMC: 3973098. DOI: 10.1172/JCI73531. View

20.

Sangeetha N, Viswanathan P, Balasubramanian T, Nalini N . Colon cancer chemopreventive efficacy of silibinin through perturbation of xenobiotic metabolizing enzymes in experimental rats. Eur J Pharmacol. 2011; 674(2-3):430-8. DOI: 10.1016/j.ejphar.2011.11.008. View