Universität zu Köln

Wang, Yan, Zhao, Yue, Herbst, Andreas, Kalinski, Thomas, Qin, Jiwei, Wang, Xiaoyan, Jiang, Zhenzhong, Benedix, Frank, Franke, Sabine, Wartman, Thomas, Camaj, Peter, Halangk, Walter, Kolligs, Frank T., Jauch, Karl W., Nelson, Peter J. and Bruns, Christiane J. (2016). miR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression. Ann. Surg., 264 (5). S. 804 - 815. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1528-1140

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Abstract

Background:Chemoresistance is a main obstacle to effective esophageal cancer (EC) therapy. We hypothesize that altered expression of microRNAs (miRNAs) play a role in EC cancer progression and resistance to 5-fluorouracil (5-FU) based chemotherapeutic strategies.Methods:Four pairs of esophageal adenocarcinoma (EAC) cell lines and corresponding 5-FU resistant variants were established. The expression levels of miRNAs previously shown to be involved in the general regulation of stem cell pathways were analyzed by qRT-PCR. The effects of selected miRNAs on proliferation, apoptosis, and chemosensitivity were evaluated both in vitro and in vivo. We identified a particular miRNA and analyzed its putative target genes in 14 pairs of human EC tumor specimens with surrounding normal tissue by qRT-PCR as well as Wnt pathway associated genes by immunohistochemistry in another 45 EAC tumor samples.Results:MiR-221 was overexpressed in 5-FU resistant EC cell lines as well as in human EAC tissue. DKK2 was identified as a target gene for miR-221. Knockdown of miR-221 in 5-FU resistant cells resulted in reduced cell proliferation, increased apoptosis, restored chemosensitivity, and led to inactivation of the Wnt/-catenin pathway mediated by alteration in DKK2 expression. Moreover, miR-221 reduction resulted in alteration of EMT-associated genes such as E-cadherin and vimentin as well as significantly slower xenograft tumor growth in nude mice. RT2 profiler analysis identified a substantial dysregulation of 4 Wnt/-catenin signaling and chemoresistance target genes as a result of miR-221 modulation: CDH1, CD44, MYC, and ABCG2.Conclusion:MiR-221 controls 5-FU resistance of EC partly via modulation of Wnt/-catenin-EMT pathways by direct targeting of DKK2 expression. MiR-221 may serve as a prognostic marker and therapeutic target for patients with 5-FU resistant EAC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wang, Yan UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Yue UNSPECIFIED UNSPECIFIED UNSPECIFIED Herbst, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalinski, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Qin, Jiwei UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Xiaoyan UNSPECIFIED UNSPECIFIED UNSPECIFIED Jiang, Zhenzhong UNSPECIFIED UNSPECIFIED UNSPECIFIED Benedix, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Franke, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Wartman, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Camaj, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Halangk, Walter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolligs, Frank T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jauch, Karl W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nelson, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, Christiane J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-257551
DOI:	10.1097/SLA.0000000000001928
Journal or Publication Title:	Ann. Surg.
Volume:	264
Number:	5
Page Range:	S. 804 - 815
Date:	2016
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1528-1140
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CATENIN SIGNALING PATHWAY; SQUAMOUS-CELL CARCINOMA; CANCER STEM-CELLS; HEPATOCELLULAR-CARCINOMA; MESENCHYMAL TRANSITION; CHEMOTHERAPY RESISTANCE; MICRORNA SIGNATURES; COLORECTAL-CANCER; PANCREATIC-CANCER; DRUG-RESISTANCE Multiple languages Surgery Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25755