Research Report
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World J Gastroenterol. Oct 28, 2014; 20(40): 14904-14912
Published online Oct 28, 2014. doi: 10.3748/wjg.v20.i40.14904
MicroRNA signatures in chemotherapy resistant esophageal cancer cell lines
Richard Hummel, Corina Sie, David I Watson, Tingting Wang, Alfiya Ansar, Michael Z Michael, Mark Van der Hoek, Joerg Haier, Damian J Hussey
Richard Hummel, Corina Sie, David I Watson, Tingting Wang, Alfiya Ansar, Damian J Hussey, Department of Surgery, Flinders University, Bedford Park, South Australia 5042, Australia
Richard Hummel, Department of General and Visceral Surgery, University of Muenster, 48149 Muenster, Germany
Michael Z Michael, Department of Gastroenterology and Hepatology, Flinders University, 5042 Bedford Park, South Australia, Australia
Mark Van der Hoek, Adelaide Microarray Centre, SA Pathology, 5000 Adelaide, South Australia, Australia
Joerg Haier, Comprehensive Cancer Centre, University of Muenster, 48149 Muenster, Germany
Author contributions: Hummel R participated in the conception of the study and in its design and coordination, established the chemotherapy resistant cell lines; Hummel R, Sie C, Wang T, Ansar A, Van der Hoek M and Hussey DJ conducted microarray and quantitative real-time PCR experiments for miRNA and mRNA expression analyses, performed the statistical analyses; Hummel R, Watson DI, Michael MZ, Van der Hoek M, Haier J and Hussey DJ participated in the conception of the study and in its design and coordination, participated in the interpretation of data, and helped to draft the manuscript; Wang T established the chemotherapy resistant cell lines; all authors read, revised and approved the final manuscript.
Supported by A Research Fellowship of the German Research Foundation (DFG) to Hummel R, No. Hu 1763/1-1; Funding was also obtained from a project grant from the National Health and Medical Research Council of Australia No.595964; Funding Sources (DFG, National Health and Medical Research Council of Australia)
Correspondence to: Damian J Hussey, PhD, Department of Surgery, Flinders University, Room 3D213, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia. damian.hussey@flinders.edu.au
Telephone: +61-8-82046086 Fax: +61-8-82046130
Received: March 5, 2014
Revised: May 19, 2014
Accepted: June 26, 2014
Published online: October 28, 2014
Processing time: 238 Days and 5.6 Hours
Abstract

AIM: To investigate expression of microRNA (miRNA) and potential targets in chemotherapy resistant esophageal cancer cell lines.

METHODS: An in-vitro model of acquired chemotherapy resistance in esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) cells was used, and microRNA expression profiles for cisplatin or 5-fluorouracil (5-FU) resistant variants vs chemotherapy sensitive controls were compared using microarray and quantitative real-time polymerase chain reaction (PCR). The expression of chemotherapy-relevant genes potentially targeted by the dysregulated microRNAs in the chemotherapy resistant variants was also evaluated.

RESULTS: Chemotherapy resistant sublines were found to have specific miRNA signatures, and these miRNA signatures were different for the cisplatin vs 5-FU resistant cells from the same tumor cell line, and also for EAC vs ESCC cells with resistance to the same specific chemotherapy agent. Amongst others, miR-27b-3p, miR-193b-3p, miR-192-5p, miR-378 a-3p, miR-125a-5p and miR-18a-3p were dysregulated, consistent with negative posttranscriptional control of KRAS, TYMS, ABCC3, CBL-B and ERBB2 expression via these miRNAs.

CONCLUSION: The current study supports the hypothesis that microRNA expression has an impact on chemotherapy resistance in esophageal cancer.

Keywords: Esophageal cancer; MicroRNA; Chemotherapy; Resistance; Target

Core tip: The current study demonstrates that chemotherapy resistant esophageal adeno- and squamous cell carcinoma cells present distinct microRNA (miRNA) signatures, with a number of well known resistance relevant miRNAs differentially expressed in the derived cisplatin or 5-fluorouracil resistant cell lines. Furthermore, a number of putative target genes that are known to have an impact on chemotherapy resistance are dysregulated in the chemotherapy resistant cell lines in a direction consistent with negative posttranscriptional control of target gene expression via the respective miRNA, thereby implicating a potential mediatory effect in terms of chemotherapy resistance development.