The levels of serine proteases in colon tissue interstitial fluid and serum serve as an indicator of colorectal cancer progression.

Yingying Xie,Guixue Hou,Siqi Liu,Xiaolei Lv,Yang Wang,Hongxia Zhu,Cuicui Jiang,Xiaomin Lou,Lechuang Chen,Lin Wu,Ningzhi Xu

doi:10.18632/oncotarget.8693

Abstract

The proteins in tissue interstitial fluids (TIFs) can spread into the blood and have been proposed as an ideal material to find blood biomarkers. The colon TIFs were collected from 8-, 13-, 18-, and 22-week ApcMin/+, a typical mouse model of colorectal cancer (CRC), and wild-type mice. iTRAQ-based quantification proteomics was conducted to survey the TIF proteins whose abundance appeared to depend on tumor progression. A total of 46 proteins that exhibited consecutive changes in abundance were identified, including six serine proteases, chymotrypsin-like elastase 1 (CELA1), chymotrypsin-like elastase 2A (CEL2A), chymopasin, chymotrypsinogen B (CTRB1), trypsin 2 (TRY2), and trypsin 4 (TRY4). The observed increases in the abundance of serine proteases were supported in another quantitative evaluation of the individual colon TIFs using a multiple reaction monitor (MRM) assay. Importantly, the increases in the abundance of serine proteases were also verified in the corresponding sera. The quantitative verification of the serine proteases was further extended to the clinical sera, revealing significantly higher levels of CELA1, CEL2A, CTRL/chymopasin, and TRY2 in CRC patients. The receiver operating characteristic analysis illustrated that the combination of CELA1 and CTRL reached the best diagnostic performance, with 90.0% sensitivity and 80.0% specificity. Thus, the quantitative target analysis demonstrated that some serine proteases are indicative of CRC progression.

Highlights

Colorectal cancer (CRC) is one of the most dangerous cancers and characterized by a high incidence and mortality [1]
The colon tissue interstitial fluids (TIFs) were collected from 8, 13, 18, and 22-week ApcMin/+, a typical mouse model of colorectal cancer (CRC), and wild-type mice. iTRAQ-based quantification proteomics was conducted to survey the TIF proteins whose abundance appeared to depend on tumor progression
Among the 20 consecutively increased proteins, we found six proteins, chymotrypsin-like elastase 1 (CELA1), chymotrypsin-like elastase 2A (CEL2A), chymopasin, CTRB1, trypsin 2 (TRY2), and trypsin 4 (TRY4), that belonged to the same serine protease family and exhibited the exactly same change patterns (Figure 3C and 3D), suggesting that the changes in the protein levels of this family tightly correlated with CRC progression

Summary

Introduction

Colorectal cancer (CRC) is one of the most dangerous cancers and characterized by a high incidence and mortality [1]. CRC is currently diagnosed using three main methods: colonoscopy, fecal occult blood testing (FOBT), and biomarker detection. As a gold standard screening method, colonoscopy can detect subtle abnormal changes in the morphology of the intestinal epithelial layer and greatly improve the CRC diagnosis rate to over 50.0% [2,3,4]. FOBT is an employed diagnostic method reported to reduce CRC mortality by approximately 20% [5], but its sensitivity and specificity for CRC, especially for early CRC, are poor because early precancerous lesions produce less occult blood in stool, whereas some nonwww.impactjournals.com/oncotarget cancerous intestinal diseases cause serious hemafecia [6]. CRC diagnosis based on protein biomarkers in the serum has become an attractive area of study because cancer-related biomarkers are specific and blood-based assays are manipulated. Technical challenges are inevitable, such as those associated with globally surveying CRC-related proteins in the serum and the efficient verification of candidate biomarkers

Methods

Results

Conclusion