Abstract
Simple SummaryOur study shows ZP2 to be a new biomarker for diagnosis, best used in combination with other low abundant genes in colon cancer. Furthermore, ZP2 promotes cell proliferation via the ERK1/2-cyclinD1-signaling pathway. We demonstrate that ZP2 mRNA is expressed in a low-abundant manner with high specificity in subsets of cancer cell lines representing different cancer subtypes and also in a significant proportion of primary colon cancers. The potential benefit of ZP2 as a biomarker is discussed. In the second part of our study, the function of ZP2 in cancerogenesis has been analyzed. Since ZP2 shows an enhanced transcript level in colon cancer cells, siRNA experiments have been performed to verify the potential role of ZP2 in cell proliferation. Based on these data, ZP2 might serve as a new target molecule for cancer diagnosis and treatment in respective cancer types such as colon cancer.Background: Zona pellucida protein ZP2 has been identified as a new colon tumor biomarker. Its transcripts were specifically expressed in four out of four human colon cancer cell lines and enhanced in about 60% of primary colon cancer tissues when compared to matched healthy ones. ZP2 down-regulation by siRNA led to a decreased proliferation rate, EXOSC5 transcript, cyclin D1 protein level, and ERK1/2 phosphorylation state. Methods: Sensitivity and quantitative expression analysis of ZP2 transcripts in tumor and matched normal colon tissue was performed with respective cDNA preparations. Silencing RNA effects on colon cancer cells were examined by q-PCR, western blot, and proliferation rate experiments. Results: In a significant portion of 69 primary colon tumor samples, the molecule showed a low but specific expression, which revealed a sensitivity value of around 90% and a specificity value of 30% when matched to the respective normal counterparts. Down-regulation of ZP2 protein by siRNA led to a decreased proliferation rate, EXOSC5 and cyclin D1 level, and phosphorylation state of ERK1/2. ZP2 has also been found to be a cell membrane-bound protein. Conclusion: ZP2 shows an enhanced expression level in colon cancer tissue and, thus, can be used as a diagnostic tool, albeit in combination with other biomarkers. Its character as a membrane protein makes ZP2 even a potential target molecule for tumor therapy, especially as it positively affects colon cancer cell proliferation.
Highlights
The application of available tumor markers is rather limited, mainly because of the fact that such markers are expressed by normal cells, albeit often to a lower extent, and, do not allow a simple yes/no decision for tumor diagnosis
For the expression of low abundant genes, an extrapolation of such a scenario from single cells to cell populations makes it likely that (1) in larger cell populations, higher fluctuation rates will provoke an overall increase in the threshold of detection, which is dependent on the population size, and (2) a reduction of the population size will lower the probability of detecting an expression of the low abundant gene at all, but, when present, will increase the probability of a higher expression level
We demonstrate that ZP2 mRNA is expressed in a low-abundant manner with high specificity in (1) subsets of cancer cell lines representing different cancer subtypes and (2) a significant proportion of primary colon cancers
Summary
The application of available tumor markers is rather limited, mainly because of the fact that such markers are expressed by normal cells, albeit often to a lower extent, and, do not allow a simple yes/no decision for tumor diagnosis. The mutator phenotype as well as the presence of highly accessible chromatin adds to an increase in stochastic gene expression, a phenomenon that, in principle, is present under non-pathological conditions [4,5]. ZP2 down-regulation by siRNA led to a decreased proliferation rate, EXOSC5 transcript, cyclin D1 protein level, and ERK1/2 phosphorylation state. Results: In a significant portion of 69 primary colon tumor samples, the molecule showed a low but specific expression, which revealed a sensitivity value of around 90% and a specificity value of 30% when matched to the respective normal counterparts. Down-regulation of ZP2 protein by siRNA led to a decreased proliferation rate, EXOSC5 and cyclin D1 level, and phosphorylation state of ERK1/2. Its character as a membrane protein makes ZP2 even a potential target molecule for tumor therapy, especially as it positively affects colon cancer cell proliferation
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