Msi-1 is a predictor of survival and a novel therapeutic target in colon cancer.
ABSTRACT Musashi1 (Msi-1), a neural RNA-binding protein, plays an important role in regulating cell differentiation in precursor cells. Recently, aberrant expression of Msi-1 has been detected in several malignancies. However, its role in the progression of colon cancer is largely unknown.
We used Western blotting to examine Msi-1 protein expression in 8 cases of primary colon cancer lesions and paired normal colonic mucosa. Msi-1 expression and clinicopathological significance were determined by immunohistochemical staining in a tissue microarray (TMA) containing 203 cases of primary colon cancer paired with noncancerous tissue and 66 lymph node metastasis (LNM) tissues. RNAi was used to analyze the biological function of Msi-1 in vitro.
LNM tissue exhibited a striking increase in Msi-1 expression when compared with primary colon cancer and adjacent normal mucosa (87.9% vs. 64.5% vs. 16.7%, P < .001). Overexpression of Msi-1 was associated with higher clinical stage, T stage, lymph node metastasis, presence of distant metastasis, and Ki-67 positivity. Msi-1 served as an independent prognostic marker whose expression levels correlated with poorer metastasis-free survival (MFS) (HR 5.4; P < .001) and poorer overall survival (OS) (HR 3.8; P < .001). Msi-1 silencing significantly inhibited proliferation ability and attenuated the migration and invasion activity of colon cancer cells.
Our study provides the basis to explore the use of Msi-1 as a novel prognostic biomarker in colon cancer patients. Aberrant overexpression of Msi-1 during metastasis of colon cancer also suggests that it is a potential therapeutic target.
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ABSTRACT: Microtubule-associated doublecortin and CaM kinase-like-1 (DCLK1) is a novel candidate marker for intestinal stem cells. The aim of our study was to assess DCLK1 immunoreactivity in colorectal carcinogenesis and its correlation with prognosis. DCLK1 immunostaining was performed in colorectal tissue from 71 patients, including 18 adenomatous polyps, 40 primary adenocarcinomas, and 14 metastatic lesions. Each case was evaluated by a combined scoring method based on the intensity of staining (score 0-3) and the percentage of tissue staining positive (score 0-3). Immunoexpression for DCLK1 was considered as positive when the combined score was 2-6 and negative with a score of 0-1. Overall, 14/18 (78%) of polyps, 30/40 (75%) of primary adenocarcinomas, and 7/14 (50%) of distant metastases were positive for DCLK1. In adenomatous polyps and primary cancer there was no association between DCLK1 staining score and tumor pathology. However, after curative colorectal cancer resection, patients whose tumor had a high (≥5) combined staining score had increased cancer-specific mortality compared to patients with low (0-4) staining score (hazard ratio 5.89; 95% confidence interval: 1.22-28.47; P = 0.027). We found that DCLK1 is frequently expressed in colorectal neoplasia and may be associated with poor prognosis. Further studies are necessary to validate the use of DCLK1 as a prognostic marker.Clinical and Experimental Gastroenterology 01/2012; 5:35-42.
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ABSTRACT: Medulloblastoma, the most common malignant brain tumor in children, is a disease whose mechanisms are now beginning to be uncovered by high-throughput studies of somatic mutations, mRNA expression patterns, and epigenetic profiles of patient tumors. One emerging theme from studies that sequenced the tumor genomes of large cohorts of medulloblastoma patients is frequent mutation of RNA binding proteins. Proteins which bind multiple RNA targets can act as master regulators of gene expression at the post-transcriptional level to co-ordinate cellular processes and alter the phenotype of the cell. Identification of the target genes of RNA binding proteins may highlight essential pathways of medulloblastomagenesis that cannot be detected by study of transcriptomics alone.Furthermore, a subset of RNA binding proteins are attractive drug targets. For example, compounds that are under development as anti-viral targets due to their ability to inhibit RNA helicases could also be tested in novel approaches to medulloblastoma therapy by targeting key RNA binding proteins. In this review, we discuss a number of RNA binding proteins, including Musashi1 (MSI1), DEAD (Asp-Glu-Ala-Asp) box helicase 3 X-linked (DDX3X), DDX31, and cell division cycle and apoptosis regulator 1 (CCAR1), which play potentially critical roles in the growth and/or maintenance of medulloblastoma.Molecules and Cells 03/2014; · 2.21 Impact Factor
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ABSTRACT: Lung cancer remains one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 20%. One approach to improving survival is the identification of biomarkers to detect early stage disease. In this study, we investigated the potential of the stem cell and progenitor cell marker, Musashi1 (Msi1), as a diagnostic marker and potential therapeutic target for lung cancer. Functional studies in A549 bronchioalveolar carcinoma and NCI-H520 squamous cell carcinoma cells revealed that Msi1 was enriched in spheroid cultures of tumor cells and in the CD133+ cell population. Downregulation of Msi1 by lentivirus-mediated expression of an Msi1 shRNA reduced spheroid colony proliferation. Growth inhibition was associated with reduced nuclear localization of β-catenin and inhibition of the processing of intracellular Notch. In primary lung cancer, Msi1 protein expression was elevated in 86% of 202 tissue microarray specimens, and Msi1 mRNA was increased in 80% of 118 bronchoscopic biopsies, including metastatic disease, but was rarely detected in adjacent normal lung tissue and in non-malignant diseased tissue. Msi1 was expressed in a diffuse pattern in most tumor subtypes, except in squamous cell carcinomas, where it appeared in a focal pattern in 50% of specimens. Thus, Msi1 is a sensitive and specific diagnostic marker for all lung cancer subtypes.Oncotarget 05/2013; · 6.64 Impact Factor