Differential gene expression identifies KRT7 and MUC1 as potential metastasis-specific targets in sarcoma
Received 7 June 2019
Accepted for publication 7 August 2019
Published 9 September 2019 Volume 2019:11 Pages 8209—8218
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Cristina Weinberg
Peer reviewer comments 2
Editor who approved publication: Dr Sanjeev Srivastava
Long Jiang*,1, Bhairavi Tolani*,1, Che-Chung Yeh1, Yanying Fan1, Joseph A Reza1, Andrew E Horvai2, Endi Xia1, Johannes R Kratz1, David M Jablons1, Michael J Mann1
1Thoracic Oncology Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA; 2Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
*These authors contributed equally to this work
Correspondence: Bhairavi Tolani; Michael J Mann
Thoracic Oncology Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA
Tel +1 415 885 3882
Background: Despite numerous discoveries regarding the molecular genesis and progression of primary cancers, the biology of metastasis remains poorly understood. Compared to very large numbers of circulating tumor cells that are now known to accompany nearly all cancers, a relatively limited number of lesions actually develop in most patients with metastases. We hypothesized that phenotypic changes driven by differential gene expression in a finite subpopulation of tumor cells render those cells capable of metastasis and sought to identify key pathways through analysis of gene expression in primary and metastatic lesions from the same patients.
Methods: We compared whole-genome expression in 4 matched samples of primary and metastatic sarcoma, then evaluated candidate genes with differential expression via quantitative PCR in 30 additional matched sets, tumor tissue immunostaining, siRNA loss-of-function in a sarcoma cell migration assay, and clinical correlation with overall and disease-free survival after metastasectomy.
Results: Comparison of microarray signals identified differential expression of cell adhesion genes, including upregulation of KRT7 and MUC1 in metastases; KRT7 and MUC1 upregulation was confirmed in 22 (73%) and 20 (67%) matched sets of metastatic/primary tumors, respectively. Silencing of KRT7 and MUC1 via targeted siRNAs suppressed sarcoma cell migration in vitro, and a significant correlation (two-sided) was observed between both KRT7 and MUC1 expression in metastases and overall patient survival.
Conclusion: KRT7 and MUC1 may play a significant role in enabling sarcoma metastasis, and they may therefore be important prognostic biomarkers as well as potential targets for therapeutic prevention of metastasis.
Keywords: sarcomas, differential expression, metastasis, microarray, MUC1, KRT7
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