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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- "The human genome encodes approximately 30 DEAD-box RNA helicases, which metabolize ATP to unwind RNA and/or remodel RNA-protein complexes (Putnam and Jankowsky, 2013). These proteins can also clamp onto RNA, thus serving as a scaffold for the assembly of larger RNA-protein complexes (Linder and Jankowsky, 2011). RNA helicases perform a diverse variety of functions in the cell, and mutations in these genes have previously been linked to cancer (Abdelhaleem, 2004). "
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.Moleculer Cells 03/2014; 37(5). DOI:10.14348/molcells.2014.0008 · 2.24 Impact Factor
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ABSTRACT: Infiltrative growth pattern at the tumor margin has been associated with shorter patient survival. However, little is known about the prognostic significance of tumor growth pattern, independent of tumoral molecular alterations and other histologic features. Utilizing a database of 1139 colon and rectal cancer patients in two prospective cohort studies, histologic features including tumor growth pattern, tumor differentiation, lymphocytic reaction, mucinous component, and signet ring cell component were recorded by a single pathologist. Cox proportional hazard model was used to compute mortality hazard ratio, adjusting for clinical, pathologic, and tumor molecular features, including microsatellite instability, the CpG island methylator phenotype, long interspersed nucleotide element 1 (LINE-1) methylation, and KRAS, BRAF, and PIK3CA mutations. Among 1139 colorectal cancers, we observed expansile growth pattern in 372 tumors (33%), intermediate growth pattern in 610 tumors (54%), and infiltrative growth pattern in 157 tumors (14%). Compared to patients with expansile growth pattern, those with infiltrative growth pattern experienced shorter cancer-specific survival (log rank P < 0.0001; multivariate hazard ratio 1.74; 95% confidence interval 1.22-2.47) and overall survival (log rank P < 0.0001; multivariate hazard ratio 1.78; 95% confidence interval 1.33-2.39). The prognostic association of infiltrative growth pattern was confined to patients with stage I-III disease (P (interaction) with stage = 0.0001). Infiltrative growth pattern was associated with worse prognosis among stage I-III colorectal cancer patients, independent of other clinical, pathologic, and molecular characteristics.Annals of Surgical Oncology 12/2011; 19(6):1944-53. DOI:10.1245/s10434-011-2174-5 · 3.94 Impact Factor
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ABSTRACT: Transcription factor Snail has been shown to promote tumor progression and metastasis in various cancers. However, its clinical significance in nasopharyngeal carcinoma (NPC) is still scanty. We have explored the clinical significance of Snail expression and its association with patient outcome in NPC. Immunohistochemistry was used to examine the expression levels of Snail in 122 patients with NPC. Cytoplasmic Snail was detected in 37.7 %, and nuclear staining was detected in 49.2 % of primary tumors, respectively. No significant associations were found between cytoplasmic Snail and the clinicopathologic variables except lymph node metastasis (P = 0.042). However, nuclear Snail was significantly associated with tumor stage (P = 0.003), T classification (P = 0.045), lymph node metastasis (P = 0.019), distant metastasis (P = 0.003), and reduced E-cadherin expression (P = 0.021). Patients with high nuclear Snail expression, but not cytoplasmic staining, had significantly shorter survival than those with low expression (P < 0.001). Significantly, nuclear Snail was an independent prognostic predictor for NPC (P < 0.001). Furthermore, the prognostic impact was largely limited to stage III-IV patients. We demonstrated first that nuclear Snail, but not cytoplasmic staining, predicts worse outcome. In addition, the prognostic value in stage III-IV suggests that nuclear Snail could be a potential therapeutic target for late stage of NPC patients.Annals of Surgical Oncology 04/2012; 19(9):2971-9. DOI:10.1245/s10434-012-2347-x · 3.94 Impact Factor