10779/rcsi.10792088.v1
Matthias PA Ebert
Matthias PA
Ebert
Marc Tänzer
Marc
Tänzer
Benjamin Balluff
Benjamin
Balluff
Elke Burgermeister
Elke
Burgermeister
Antje Karen Kretzschmar
Antje Karen
Kretzschmar
David J. Hughes
David J.
Hughes
Reimo Tetzner
Reimo
Tetzner
Catherine Lofton-Day
Catherine
Lofton-Day
Robert Rosenberg
Robert
Rosenberg
Anke C. Reinacher-Schick
Anke C.
Reinacher-Schick
Karsten Schulmann
Karsten
Schulmann
Andrea Tannapfel
Andrea
Tannapfel
Ralf Hofheinz
Ralf
Hofheinz
Christoph Röcken
Christoph
Röcken
Gisela Keller
Gisela
Keller
Rupert Langer
Rupert
Langer
Katja Specht
Katja
Specht
Rainer Porschen
Rainer
Porschen
Jan Stöhlmacher-Williams
Jan
Stöhlmacher-Williams
Tibor Schuster
Tibor
Schuster
Philipp Ströbel
Philipp
Ströbel
Roland M. Schmid
Roland M.
Schmid
TFAP2E-DKK4 and chemoresistance in colorectal cancer.
Royal College of Surgeons in Ireland
2019
Aged
Antineoplastic Agents
Cell Line
Tumor
Chemoradiotherapy
Colorectal Neoplasms
DNA
DNA Methylation
Drug Resistance
Neoplasm
Epigenesis
Genetic
Female
Gene Expression
Gene Expression Regulation
Neoplastic
Humans
Intercellular Signaling Peptides and Proteins
Male
Microsatellite Instability
Middle Aged
Mutation
Transcription Factor AP-2
Physiology
Medical Physics
2019-11-22 17:01:10
Journal contribution
https://repository.rcsi.com/articles/journal_contribution/TFAP2E-DKK4_and_chemoresistance_in_colorectal_cancer_/10792088
<p>BACKGROUND: Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy.</p>
<p>METHODS: We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation.</p>
<p>RESULTS: TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P</p>
<p>CONCLUSIONS: TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance. (Funded by Deutsche Forschungsgemeinschaft and others.).</p>