Stratifying risk of recurrence in stage II colorectal cancer using deregulated stromal and epithelial microRNAs
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Marc D. Bullock1,4, Karen Pickard1, Richard Mitter2, A. Emre Sayan1, John N. Primrose1,4, Cristina Ivan3, George A. Calin3, Gareth J. Thomas1, Graham K. Packham1, Alex H. Mirnezami1,4
1University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Southampton, UK
2Bioinformatics Unit, London Research Institute, Cancer Research UK, London, UK
3Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Surgery, Southampton University Hospital NHS Trust, Southampton, UK
Alex H. Mirnezami, e-mail: [email protected]
Keywords: Colorectal cancer, microRNA, stroma, tumor microenvironment
Received: August 18, 2014 Accepted: January 27, 2015 Published: March 07, 2015
MicroRNAs (miRNAs) enable colonic epithelial cells to acquire malignant characteristics and metastatic capabilities. Recently, cancer relevant miRNAs deregulated during disease progression have also been identified in tumor-associated stroma.
By combining laser-microdissection (LMD) with high-throughput screening and high-sensitivity quantitation techniques, miRNA expression in colorectal cancer (CRC) specimens and paired normal colonic tissue was independently characterized in stromal and epithelial tissue compartments. Notably, deregulation of the key oncogene miR-21 was identified exclusively as a stromal phenomenon and miR-106a, an epithelial phenomenon in the malignant state.
MiRNAs identified in this study successfully distinguished CRC from normal tissue and metastatic from non-metastatic tumor specimens. Furthermore, in a separate cohort of 50 consecutive patients with CRC, stromal miR-21 and miR-556 and epithelial miR-106a expression predicted short disease free survival (DFS) and overall survival (OS) in stage II disease: miR-21 (DFS: HR = 2.68, p = 0.015; OS: HR = 2.47, p = 0.029); miR-556 (DFS: HR = 2.60, p = 0.018); miR-106a (DFS: HR = 2.91, p = 0.008; OS: HR = 2.25, p = 0.049); combined (All High vs. All Low. DFS: HR = 5.83, p = 0.002; OS: HR = 4.13, p = 0.007).
These data support the notion that stromal as well as epithelial miRNAs play important roles during disease progression, and that mapping patterns of deregulated gene expression to the appropriate tumor strata may be a valuable aid to therapeutic decision making in CRC.
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