Abstract
Colorectal cancer (CRC) is a heterogeneous disease resulting from the combined influence of many genetic factors. This complexity has caused the molecular characterization of CRC to remain uncharacterized, with a lack of clear gene markers associated with CRC and the prognosis of this disease. Thus, highly sensitive tumor markers for the detection of CRC are the most essential determinants of survival. In this study, we examined the simultaneous downregulation of the mRNA levels of six metallothionein (MT) genes in CRC cell lines and public CRC datasets for the first time. In addition, we detected downregulation of these six MT mRNAs’ levels in 30 pairs of tumor (T) and adjacent non-tumor (N) CRC specimens. In order to understand the potential prognostic relevance of these six MT genes and CRC, we presented a four-gene signature to evaluate the prognosis of CRC patients. Further discovery suggested that the four-gene signature (MT1F, MT1G, MT1L, and MT1X) predicted survival better than any combination of two-, three-, four-, five-, or six-gene models. In conclusion, this study is the first to report that simultaneous downregulation of six MT mRNAs’ levels in CRC patients, and their aberrant expression together, accurately predicted CRC patients’ outcomes.
Highlights
Colorectal cancer (CRC) is the third most frequent tumor-related cause of mortality of men and women worldwide [1]
CRC is a heterogeneous disease composed of biologically and clinically diverse diseases. This complexity causes the molecular characterization of CRC to remain deficient, with a lack of clear gene markers associated with CRC and to the prognosis of this disease [19,20]
We identified for the first time that the MT1F, MT1G, MT1L, and MT1X-four-gene signature combination is related to survival and is a predictor of prognosis in CRC patients
Summary
Colorectal cancer (CRC) is the third most frequent tumor-related cause of mortality of men and women worldwide [1]. Multi-gene biomarkers may be better suited to capturing the complex effects of heterogeneous diseases such as cancer on mRNA abundance levels [8]. Our recent study showed that six metallothionein (MT) genes were among the top 20 downregulated genes in CRC clinical tissues compared with normal colorectal tissues by analysis of a Gene Expression Omnibus (GEO) dataset (GSE21815) (our unpublished data from [9]). Numerous immunohistochemical and gene expression studies have demonstrated that changes in MT expression are associated with the process of carcinogenesis in various types of human malignancies, including CRC [13,14]. Downregulation of MT expression has been revealed in association with CRC progression, the prognostic relevance of the expression levels of MTs in CRC is still unclear. In the present study, simultaneous downregulation of six MT mRNAs’ levels was examined in CRC cell lines and public CRC datasets. We further investigated the prognostic significance of these factors for CRC outcomes
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