High MCM3 expression is an independent biomarker of poor prognosis and correlates with reduced RBM3 expression in a prospective cohort of malignant melanoma

Abstract

BackgroundMalignant melanoma is the most lethal form of skin cancer with a variable clinical course even in patients with thin melanomas and localized disease. Despite increasing insights into melanoma biology, no prognostic biomarkers have yet been incorporated into clinical protocols. Reduced expression of the RNA binding motif protein 3 (RBM3) has been shown to correlate with tumour progression and poor prognosis in melanoma and several other cancer forms. In ovarian cancer, an inverse association was found between expression of RBM3 and the minichromosome maintenance 3 (MCM3) gene and protein. In melanoma, gene expression analysis and immunohistochemical validation has uncovered MCM3 as a putative prognostic biomarker. The aim of the present study was to examine the associations of MCM3 expression with clinical outcome and RBM3 expression in a prospective, population-based cohort of melanoma.MethodsImmunohistochemical MCM3 expression was examined in 224 incident cases of primary melanoma from the Malmö Diet and Cancer Study, previously analysed for RBM3 expression. Spearman´s Rho and Chi-Square tests were used to explore correlations between MCM3 expression, clinicopathological factors, and expression of RBM3 and Ki67. Kaplan Meier analysis, the log rank test, and univariable and multivariable Cox proportional hazards modelling were used to assess the impact of MCM3 expression on disease-free survival (DFS) and melanoma-specific survival (MSS).ResultsHigh MCM3 expression was significantly associated with unfavourable clinicopathological features and high Ki67 expression. A significant inverse correlation was seen between expression of MCM3 and RBM3 (p = 0.025). High MCM3 expression was associated with a reduced DFS (HR = 5.62) and MSS (HR = 6.03), and these associations remained significant in multivariable analysis, adjusted for all other factors (HR = 5.01 for DFS and HR = 4.96 for MSS). RBM3 expression remained an independent prognostic factor for MSS but not DFS in the multivariable model.ConclusionsThese findings provide validation of the utility of MCM3 expression as an independent biomarker for prognostication of patients with primary melanoma. Moreover, the inverse association and prognostic impact of MCM3 and RBM3 expression indicate a possible interaction of these proteins in melanoma progression, the functional basis for which merits further study.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1814908129755401

Stress-Response Protein RBM3 Attenuates the Stem-like Properties of Prostate Cancer Cells by Interfering with CD44 Variant Splicing

“…For example, while RBM3 is thought to be a proto-oncogene that is upregulated in many cancers where it appears to protect cancer cells from mitotic catastrophe (19) or apoptosis (33), several studies also show that high RBM3 expression in cancer cells, especially in the nucleus, predicts a better prognosis in a variety of cancers, including prostate cancer (34)(35)(36)(37)(38)(39)(40). This negative correlation between RBM3 expression and tumor progression does not seem to support its oncogenic function but is in agreement with the present results showing decreased RBM3 expression in metastatic prostate cancer compared with primary cancer and, more importantly, that overexpression of RBM3 in PC3 cells greatly attenuates the stem cell-like feature of this aggressive cell line.…”

Loss of RNA‐binding motif protein 3 expression is associated with right‐sided localization and poor prognosis in colorectal cancer

“…RBM3 overexpression is related to decreased cell death and increased cell proliferation . Immunohistochemical studies have shown that high nuclear RBM3 expression is associated with improved prognosis in an array of human malignancies, including melanoma, and breast, ovarian, oesophageal, gastric and urothelial bladder cancer . In prostate cancer, different prognostic impacts of RBM3 immunostaining results have been reported.…”

“…7 Immunohistochemical studies have shown that high nuclear RBM3 expression is associated with improved prognosis in an array of human malignancies, including melanoma, and breast, ovarian, oesophageal, gastric and urothelial bladder cancer. [8][9][10][11][12][13][14][15] In prostate cancer, different prognostic impacts of RBM3 immunostaining results have been reported. Whereas one study suggested high RBM3 expression to be a good prognostic sign, 16 another recent large study on operated prostate cancer showed that high RBM3 expression is an independent prognostic marker of early biochemical recurrence, and is tightly linked to ERG activation and PTEN deletions.…”

Ki-67 protein predicts survival in oral squamous carcinoma cells: an immunohistochemical study

“…Recently, our research group has shown that MCM3 represents a useful proliferation biomarker to evaluate the progression of dysplastic lesions 8 . Previous studies have reported that some MCM family proteins may be associated with overall survival in various cancers such as gliomas, malignant melanoma, anaplastic astrocytoma and medulloblastoma 29,32,33,34 . Conversely, Ahn et al 35 did not find any relationship between the expression of MCM family proteins and overall survival in cases of squamous cell carcinoma of the esophagus.…”