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Role of SMC1A overexpression as a predictor of poor prognosis in late stage colorectal cancer.

ABSTRACT: Structural maintenance of chromosomes 1A (SMC1A) is a member of the cohesion family of proteins that plays crucial roles in cell cycle control. Recent studies have concluded that SMC1A is involved in the pathogenesis of cancer. This study aims to evaluate the functional role of SMC1A in colorectal cancer (CRC) both in vitro and in vivo, and the underlying molecular mechanisms.We firstly investigated the expression levels of SMC1A in 427 CRC specimens. Antigen expression was determined by immunohistochemical analysis of SMC1A on tissue microarrays. Stable SMC1A knockdown CRC cell lines were employed. The effects of SMC1A depletion on cell growth in vitro were examined by MTT, colony formation and flow cytometry assays. Tumor forming was evaluated by nude mice model in vivo. To detect the activation of intracellular signaling, pathscan intracellular signaling array and western blotting were performed.The expression of SMC1A was much stronger in CRC tumor tissues than in adenomas and normal colorectal tissues. High SMC1A expression, indicated as an independent poor prognostic predictor for patients with stage III and stage IV CRC, was correlated with overall survival (OS) (p?=?0.008). Functional analysis indicated that SMC1A knockdown by small interfering RNA (siRNA) mediated the significant inhibition of cell proliferation; induced cell cycle arrest and apoptosis via the suppression of CDK4, PCNA and PARP; and blocked the activation of the Erk1/2 and Akt cascades in CRC cells. In addition, SMC1A depletion significantly decreased the growth of subcutaneously inoculated tumors in nude mice.These results suggest that SMC1A plays an essential role in the development of CRC and may be a predictive factor in patients with CRC. The inhibition of SMC1A may serve as a promising therapeutic strategy for human CRC.

SUBMITTER: Wang J

PROVIDER: S-EPMC4352287 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Role of SMC1A overexpression as a predictor of poor prognosis in late stage colorectal cancer.

Wang Jianwei J Yu Shaojun S Cui Liming L Wang Wenhui W Li Jun J Wang Ke K Lao Xinyuan X

BMC cancer 20150304

<h4>Background</h4>Structural maintenance of chromosomes 1A (SMC1A) is a member of the cohesion family of proteins that plays crucial roles in cell cycle control. Recent studies have concluded that SMC1A is involved in the pathogenesis of cancer. This study aims to evaluate the functional role of SMC1A in colorectal cancer (CRC) both in vitro and in vivo, and the underlying molecular mechanisms.<h4>Methods</h4>We firstly investigated the expression levels of SMC1A in 427 CRC specimens. Antigen e ...[more]

PMID: 25884313

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Project description:BackgroundThe long non-coding RNA (lncRNA) prostate cancer-associated transcript 6 (PCAT6) has been studied in many cancers, yet its relationship with colorectal cancer (CRC) remains poorly defined. Here, we conducted an analysis of The Cancer Genome Atlas (TCGA) database to better clarify the role of PCAT6 in this cancer type.MethodsWilcoxon rank-sum tests were utilized to assess relative levels of PCAT6 in CRC tumors and normal tissues, while logistic regression analyses were utilized to compare the relationships between PCAT6 levels and clinicopathological findings. Kaplan-Meier curves and Cox regression analyses were used to gauge correlations between PCAT6 and patient survival outcomes, while the biological roles of this lncRNA were investigated via a gene set enrichment analysis (GSEA) approach. The expression level of PCAT6 in CRC cell lines was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR).ResultsPCAT6 levels were significantly correlated with CRC patient lymph node metastasis (N) stage [odds ratio (OR) =1.8 for N1 & N2 vs. N0], lymphatic invasion [OR =1.9 for yes vs. no), distant metastasis (M stage) (OR =2.1 for M1 vs. M0), carcinoembryonic antigen (CEA) level (OR =1.9 for >5 vs. ≤5), perineural invasion (OR =1.9 for yes vs. no), pathologic stage (OR =1.9 for stage III/IV vs. stage I/II), and neoplasm type (OR =2.1 for rectal adenocarcinoma vs. colon adenocarcinoma) (all P<0.05). CRC patients expressing higher PCAT6 levels exhibited poorer survival outcomes than those expressing low levels of this lncRNA (P=0.017), and in univariate analyses, higher PCAT6 levels were linked to worse overall survival [hazard ratio (HR) =1.540; 95% confidence interval (CI): 1.079-2.199; P=0.017], with this relationship also being preserved in a multivariate analysis (HR =6.892; 95% CI: 1.713-27.727, P=0.007). GSEA revealed high PCAT6 expression to be linked to differential DNA methylation enrichment, with high PCAT6 levels being associated with changes in base excision repair, cellular senescence, G2/M DNA damage checkpoint, chromatin-modifying enzyme, and gene silencing by RNA activity. The high expression of lncRNA PCAT6 in CRC cell lines was demonstrated by PCR experiments.ConclusionsPCAT6 represents a promising prognostic biomarker of poor CRC patient survival outcomes, with DNA methylation and RNA-mediated gene silencing being potentially promising mechanistic pathways whereby this lncRNA may shape patient outcomes.

Project description:BackgroundBladder cancer is one of the most common urinary malignancies. This study is aimed at providing some promising molecular biomarkers for bladder cancer (BC) by investigating the correlation between C1QTNF6 expression and clinical characteristics as well as prognosis in patients with bladder cancer.MethodsSequencing profiles of C1QTNF6 mRNA in BC patients were collected to evaluate the distinctive gene expression, between normal bladder mucosa and BC, according to the TCGA and GEO databases. The association between C1QTNF6 expression and the clinical features as well as the disease prognosis was evaluated using two independent cohorts. The expression of C1QTNF6 in normal bladder and BC cells was examined by western blotting and PCR, so the underlying molecular mechanism could be further investigated.ResultsC1QTNF6 mRNA levels were found to be differentially expressed in two independent public cohorts, including the TCGA database and GSE13507 dataset from GEO. The protein and RNA levels of C1QTNF6 in BC cells were both elevated when compared to normal bladder cell lines. High C1QTNF6 expression was detected in advanced T/M stages, pathological grade, and AJCC stage when compared to the low C1QTNF6 expression group. The underlying mechanism related to this differential expression could be explained by cell migration and invasion assays, where bladder cancer cells 5637 and T24 had a significant reduction on migration and invasion ability upon knockdown of C1QTNF6 expression. The low C1QTNF6 expression group presented a more prominent OS advantage over the high-expression group in both TCGA and GSE13507 cohorts. Moreover, the protein content in tissues was further validated using the HPA database and TMA. Survival analyses also indicated that the high C1QTNF6 expression group had an unfavorable OS when compared to the low-expression group.ConclusionsHigh C1QTNF6 expression may serve as a predictor of poor prognosis in bladder cancer patients, and the underlying mechanism is possibly associated with changes on cancer cell migration and invasion ability.

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Role of SMC1A overexpression as a predictor of poor prognosis in late stage colorectal cancer.

Publications

Role of SMC1A overexpression as a predictor of poor prognosis in late stage colorectal cancer.

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