Abstract
Abstract Protein posttranslational modification (PTM) plays a pivotal role in cancer progression through regulating gene expression, protein activities and stabilization. These chemistry events are regarded as potential biomarkers for cancer diagnosis, prognosis, and therapeutic efficacy evaluation. Hydroxylated proline is the most common PTM amino acid residue in the proteome. However, this modification is often overlooked. Here, we demonstrate the expression level of prolyl-4-hydroxylase alpha-1(P4HA1) in tumor tissues and the ratio of its catalyst (hydroxyprolyl-3-bradykinin, Hyp-BK) to its substrate (bradykinin, BK) in blood can serve as biomarkers for early pancreatic cancer diagnosis. First, we found that the P4HA1 expression level responds to the activation of KRAS which is commonly observed in pancreatic cancer cells. Immunohistochemistry testing for tumor tissue array reveals that pancreatic cancer tumor tissues, even in stage I tumor, present higher P4HA1 expression levels than tissues with chronic pancreatitis and healthy control. Peptidomic studies on clinical blood samples revealed that the Hyp-BK/BK value was 2.3 fold higher in pancreatic cancer patients than chronic pancreatitis patients and control group. The results were further validated in an independent sample cohort with blind information. We combined CA19-9 and the Hyp-BK/BK value as a biomarker panel obtaining an area under the curve (AUC) of 0.742 and 0.813 in the comparison of pancreatic cancer to pancreatitis patients and controls, respectively. Our results demonstrate that the measurement of Hyp-BK/BK value in blood, which reflects the hydroxylation level regulated by tumor-localized P4HA1, can be used as a biomarker for early detection of pancreatic cancer. Citation Format: Zaian Deng, Karen M. Mann, Eugene J. Koay, Mauro Ferrari, Xifeng Wu, Paul J. Chiao, Tony Hu. KRAS-regulated P4HA1 in pancreatic tumor and its hydroxylated peptide as a serum biomarker for early diagnosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1833. doi:10.1158/1538-7445.AM2015-1833
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