Abstract
Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) encodes an enzyme that catalyzes de novo purine biosynthesis. Although PAICS has been implicated as a potential therapeutic target in several cancers, its clinical and prognostic significance in colorectal cancer (CRC) is not fully understood. To elucidate the roles of PAICS in CRC, we investigated PAICS expression in four cohorts consisting of a total of 1659 samples based on quantitative RT-PCR, microarray and RNA-seq analysis. Despite upregulated PAICS levels in tumor compared to those of normal mucosa, we found a decreasing trend of PAICS expression during tumor progression and metastasis. We conducted immunohistochemistry on 252 specimens, showing that PAICS protein was strongly expressed in the majority of CRCs, but not in adjacent mucosa. Notably, 29.0% of tumors lacked PAICS staining, and PAICS-negative expression in tumor had significant prognostic impact on poor cancer-specific survival in stage III CRC. Correspondingly, decreased levels of PAICS transcript were also correlated with poor relapse-free survival particularly in stage III patients, and this finding was robustly confirmed in three microarray datasets of a total of 802 stage II-III patients. Bioinformatics analysis of CRC tissues and cell lines consistently indicated a correlation between decreased PAICS expression and copy number loss of chromosome arm 4q. In conclusion, our results suggest that PAICS expression is downregulated during tumor progression due to genetic deletion of chromosome 4q in microsatellite stable but chromosomally unstable tumors. Furthermore, decreased expression of PAICS transcript or loss of PAICS protein may provide prognostic stratification for postoperative patients with stage III CRC.
Highlights
Colorectal cancer (CRC) is one of the most common types of cancer, with an estimated annual incidence of over 1.8 million cases and over 880,000 deaths worldwide [1]
In the Memorial Sloan-Kettering (MSK) cohort analyzed on Affymetrix microarray, as shown in Fig 1B, we confirmed that phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) was significantly overexpressed in colon adenomas and CRCs compared to those of normal mucosa (P
We addressed the clinical and prognostic significance of PAICS in CRC using multiple cohorts based on different platforms, leading to the identification of decreased PAICS expression and loss of PAICS protein as novel prognostic biomarkers for poor survival outcome, especially in patients with stage III CRC
Summary
Colorectal cancer (CRC) is one of the most common types of cancer, with an estimated annual incidence of over 1.8 million cases and over 880,000 deaths worldwide [1]. A substantial proportion of these patients do not recur when treated with surgery alone, whereas others develop recurrence and death even after curative surgery followed by adjuvant chemotherapy [2,3]. Such clinically heterogeneous outcomes may reflect molecular heterogeneity among tumors. Colorectal carcinogenesis is driven by multiple genetic and epigenetic changes in tumor cells in association with genomic instability, namely, chromosomal instability (CIN) or microsatellite instability (MSI) [2,5,6]. 15% of CRCs with high-level microsatellite instability (MSI-H) exhibit hypermutation but typically lack CIN [5]
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