Decreased expression of MT1E is a potential biomarker of prostate cancer progression

Abstract

Differentiation of indolent and aggressive prostate carcinoma (PCa) at the time of diagnosis is currently one of the major challenges. This study aimed at identification of prognostic biomarkers to aid in predicting biochemical recurrence (BCR) of the disease. Microarray-based gene expression profiling in tissues of 8 BCR and 8 No-BCR cases revealed expression differences of 455 genes, most of which were down-regulated in BCR cases. Eleven genes were selected for validation by real-time PCR in the first PCa cohort (N = 55), while seven of them were further validated in the second, independent, PCa cohort (N = 53). Down-regulation of MT1E (p < 0.001) and GPR52 (p = 0.002) expression and up-regulated levels of EZH2 (p = 0.025) were specific biomarkers of BCR in at least one of the two PCa cohorts, but only MT1E expression retained the independent prognostic value in a multivariate analysis (p < 0.001). DNA methylation analysis (114 PCa and 24 non-cancerous tissues) showed frequent MT1E methylation in PCa (p < 0.001) and was associated (p < 0.010) with the down-regulated expression in one PCa cohort. The results of our study suggest MT1E down-regulation as a potential feature of aggressive PCa.

The roles of metallothioneins in carcinogenesis

“…When MTs bind to physiological heavy metals, such as zinc and copper, they can participate in regulating cell growth and proliferation and protecting the body against oxidative stress [ 5 ]. Recently, many studies have shown that MT expression varies in different tumors, suggesting that MTs may play a vital role in carcinogenesis [ 6 – 10 ]. The elucidation of possible functions and mechanisms of MTs in tumor progression may provide potential promising markers for cancer.…”

“…However, in other types of cancers such as prostate cancer [ 10 ], hepatocellular carcinoma [ 133 , 134 ], and gastric cancer [ 135 ], the downregulation of MT expression was associated with poor prognosis. Demidenko and colleagues attempted to identify the prognostic biomarkers for predicting biochemical recurrence (BCR) of prostate cancer.…”

“…They identified 455 differentially expressed genes through global gene expression profiling, among which seven genes ( CHI3L2 , FABP7 , GHRH , GPR52 , MT1E , OLR1 , and SAA2 ) were selected for further validation in two independent prostate cancer cohorts. The results suggested that MT1E downregulation was a potential biomarker of early BCR and poor prognosis in prostate cancer patients [ 10 ]. Park and Yu demonstrated that MT1 and MT2 are important prognostic markers in hepatocellular carcinoma.…”

“…Numerous studies have demonstrated that the elimination of tumor suppressor gene activity by promoter methylation is responsible for carcinogenesis, a mechanism that has been confirmed in many human cancers. Demidenko et al revealed MT1E promoter methylation as a possible mechanism of gene inactivation, which resulted in the reduced expression of MT1E in prostate cancer [ 10 ]. Similar observations were validated in patients with endometrial carcinoma [ 143 ] and melanoma [ 144 ].…”

DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma

“…Various studies also revealed that metallothionein expression is not universal for different cancer types. Specifically, metallothionein genes are frequently downregulated in liver cancer, squamous cell lung carcinoma, or prostate tumors, which could be associated with promoter DNA methylation (10)(11)(12). In contrast, increased metallothionein expression has been reported in melanoma, ovarian or breast tumors (13)(14)(15), while investigations of some other tumors produced contradictory results.…”