Identification of NUCKS1 as a colorectal cancer prognostic marker through integrated expression and copy number analysis

Abstract

We identified a novel prognostic biomarker for the distant metastasis of colorectal cancer (CRC) using comprehensive combined copy number and gene expression analyses. Expression of mRNA in CRC tissue was profiled in 115 patients using an Affymetrix Gene Chip, and copy number profiles were generated for 122 patients using an Affymetrix 250K Sty array. Genes showing both upregulated expression and copy number gains in cases involving distant CRC metastasis were extracted as candidate biomarkers. Expression of the candidate gene mRNA was validated in 86 patients using quantitative reverse transcription polymerase chain reaction assays. Expression of the protein encoded by the candidate gene was assessed using immunohistochemical staining of tissue from 269 patients. The relationship between protein expression and clinicopathologic features was also examined. Following combined copy number and gene expression analyses, three genes linked to distant metastasis of CRC were extracted as candidate biomarkers. The expression of NUCKS1, reportedly overexpressed in several cancers other than CRC, was significantly higher in CRC tissue than in normal tissue. Overexpression of the NUCKS1 protein in CRC cells was found to be associated with significantly worse overall survival and relapse-free survival, indicating that NUCKS1 is an independent risk factor for CRC recurrence. The overexpression of NUCKS1 in cancer cells could be used as a CRC prognostic marker and might also be a target for treatment of this disease.Colorectal cancer (CRC) is now the third most prevalent cancer and the second leading cause of cancer-related mortality worldwide. 1 In Japan, the incidence of CRC has doubled over the past 20 years such that CRC is now the second most deadly neoplastic disease. 2,3 Surgery is still the most effective treatment for CRC. Among those patients that undergo curative surgery, some develop local recurrence or distant metastases that lead to shorter survival times. 4 Distant metastasis has a critical influence on the prognosis of CRC. Clinicopathologic indicators such as the tumor node metastasis (TNM) classification system of the International Union Against Cancer (UICC) remain the standard for prognosis and provide the basis for therapeutic decision making. However, clinicopathologic indicators alone do not enable clinicians to make precise prognoses for individual CRC patients. 5 In order to develop personalized therapy regimens, it is therefore critical that researchers identify novel genes involved in distant metastasis that can serve as predictive biomarkers. 6 A particularly powerful tool for identifying potential biomarker genes for use in cancer prognosis is the microarray. 7-9 It is now possible with microarray analysis to investigate several thousand cancer-related or cancer-specific genes at once.Chromosomal structural alterations play an important role in cancer development. In CRC, copy number aberrations (CNAs), including gains on chromosomes 7, 8, 13 and 20, and losses on chromosomes 1p, 8p, 17p and 18, a...

PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis

“…Additionally, in primary tumors, PKLR expression was associated with the presence of metastatic disease (Figure 3, F and G) as well as the development of liver metastases ( Figure 3H; refs. [28][29][30]. These tumors totaled 284 in sum.…”

“…PKL and PKR have only been described to promote glycolysis in their respective tissues, catalyzing the final rate-limiting step, which involves the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP, generating pyruvate and ATP. Although PKLR had originally been described to be solely expressed in liver, kidney, and red blood cells (20), PKL expression has also been observed in (29,30). (H) PKLR expression, as measured by microarray in primary tumor samples of patients who were monitored over time for the development of liver metastases (28).…”

Identification of prosaposin and transgelin as potential biomarkers for gallbladder cancer using quantitative proteomics

“…It has a DNA binding activity which is under regulation of CDKs. It is observed to be upregulated in invasive ductal carcinoma of the breast and colorectal cancers [19,20]. Including DMBT1, several membrane and extracellular proteins were upregulated in gallbladder cancer.…”

The comparison of nuclear ubiquitous casein and cyclin-dependent kinases substrate (NUCKS) with Ki67 proliferation marker expression in common skin tumors

“…The elevated expression of the NUCKS gene was also found to be associated with high-invasive phenotype in mouse lung adenocarcinoma cell strains and the NUCKS protein was increased in the majority of the cell strains [12]. Additionally Kikuchi et al revealed a significant correlation between NUCKS expression level and tumor stage, CEA level and other features in patients with colorectal carcinoma [13].…”