Theranostics 2016; 6(1):65-77. doi:10.7150/thno.12350 This issue

Research Paper

Glycoproteomic Approach Identifies KRAS as a Positive Regulator of CREG1 in Non-small Cell Lung Cancer Cells

David J. Clark1,2, Yuping Mei1, Shisheng Sun3, Hui Zhang3, Austin J. Yang2, Li Mao1,2✉

1. Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD
2. Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD
3. Department of Pathology, John Hopkins University, Baltimore, MD

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Clark DJ, Mei Y, Sun S, Zhang H, Yang AJ, Mao L. Glycoproteomic Approach Identifies KRAS as a Positive Regulator of CREG1 in Non-small Cell Lung Cancer Cells. Theranostics 2016; 6(1):65-77. doi:10.7150/thno.12350. Available from

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Graphic abstract

Protein glycosylation plays a fundamental role in a multitude of biological processes, and the associated aberrant expression of glycoproteins in cancer has made them attractive biomarkers and therapeutic targets. In this study, we examined differentially expressed glycoproteins in cell lines derived from three different states of lung tumorigenesis: an immortalized bronchial epithelial cell (HBE) line, a non-small cell lung cancer (NSCLC) cell line harboring a Kirsten rat sarcoma viral oncogene homolog (KRAS) activation mutation and a NSCLC cell line harboring an epidermal growth factor receptor (EGFR) activation deletion. Using a Triple SILAC proteomic quantification strategy paired with hydrazide chemistry N-linked glycopeptide enrichment, we quantified 118 glycopeptides in the three cell lines derived from 82 glycoproteins. Proteomic profiling revealed 27 glycopeptides overexpressed in both NSCLC cell lines, 6 glycopeptides overexpressed only in the EGFR mutant cells and 19 glycopeptides overexpressed only in the KRAS mutant cells. Further investigation of a panel of NSCLC cell lines found that Cellular repressor of E1A-stimulated genes (CREG1) overexpression was closely correlated with KRAS mutation status in NSCLC cells and could be down-regulated by inhibition of KRAS expression. Our results indicate that CREG1 is a down-stream effector of KRAS in a sub-type of NSCLC cells and a novel candidate biomarker or therapeutic target for KRAS mutant NSCLC.

Keywords: KRAS, non-small cell lung cancer (NSCLC), adenocarcinoma, quantitative glycoproteomics, glycoprotein