Abstract
DNA damage-inducible transcript 4 (DDIT4) is induced in various cellular stress conditions. This study was conducted to investigate expression and prognostic significance of DDIT4 protein as a biomarker in the patients with colorectal cancer (CRC). PPI network and KEGG pathway analysis were applied to identify hub genes among obtained differentially expressed genes in CRC tissues from three GEO Series. In clinical, expression of DDIT4 as one of hub genes in three subcellular locations was evaluated in 198 CRC tissues using immunohistochemistry method on tissue microarrays. The association between DDIT4 expression and clinicopathological features as well as survival outcomes were analyzed. Results of bioinformatics analysis indicated 14 hub genes enriched in significant pathways according to KEGG pathways analysis among which DDIT4 was selected to evaluate CRC tissues. Overexpression of nuclear DDIT4 protein was found in CRC tissues compared to adjacent normal tissues (P = 0.003). Furthermore, higher nuclear expression of DDIT4 was found to be significantly associated with the reduced tumor differentiation and advanced TNM stages (all, P = 0.009). No significant association was observed between survival outcomes and nuclear expression of DDIT4 in CRC cases. Our findings indicated higher nuclear expression of DDIT4 was significantly associated with more aggressive tumor behavior and more advanced stage of disease in the patients with CRC.
Highlights
Colorectal cancer (CRC) as a heterogeneous disease is considered as the second leading cause of cancer-related deaths worldwide[1]
Results of the protein–protein interaction (PPI) network and enrichment analyses determined hub genes that a few of them including damage-inducible transcript 4 (DDIT4) were involved in ‘microRNAs in cancer’, a pathway in colorectal cancer (CRC) disease based on the Kyoto encyclopedia of genes and genomes (KEGG) DISEASE Database
KEGG pathway enrichment analysis revealed that DDIT4 participates in PI3K-Akt/mTOR signaling pathways as important regulators for properties of pluripotent stem cells[41]
Summary
Colorectal cancer (CRC) as a heterogeneous disease is considered as the second leading cause of cancer-related deaths worldwide[1]. Diagnostic and prognostic biomarkers are required that could be more clinically applicable rather than conventional b iomarkers[7] and stratify the patients with CRC for cancer therapy[6,8,9]. In this regard, studying character and frequency of genetic and epigenetic alterations in cancer has been used as a great tool to investigate and identify those biomarkers which are linked to tumor development and medicine a rrangements[3,9]. Upregulation of DDIT4 protein has been found to be associated with the decreased expression of pro-apoptotic proteins and at the same time the increased levels of anti-apoptotic proteins after inducing activity of RAS oncogene in ovarian epithelial cells[23,24]
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