Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), also known as nuclear-enriched transcript 2 (NEAT2), is highly conserved among mammals and highly expressed in the nucleus. It was first identified in lung cancer as a prognostic marker for metastasis but is also associated with several other solid tumors. In hepatocellular carcinoma (HCC), MALAT1 is a novel biomarker for predicting tumor recurrence after liver transplantation. The mechanism of overexpression in tumor progression remains unclear. In the present study, we investigated the role of specificity protein 1/3 (Sp1/3) in regulation of MALAT1 transcription in HCC cells. The results showed a high expression of Sp1, Sp3 and MALAT1 in HCC vs. paired non-tumor liver tissues, which was associated with the AFP level (Sp1, r=7.44, P=0.0064; MALAT1, r=12.37, P=0.0004). Co-silencing of Sp1 and Sp3 synergistically repressed MALAT1 expression. Sp1 binding inhibitor, mithramycin A (MIT), also inhibited MALAT1 expression in HCC cells. In conclusion, the upstream of MALAT1 contains five Sp1/3 binding sites, which may be responsible for MALAT1 transcription. Inhibitors, such as MIT, provide a potential therapeutic strategy for HCC patients with MALAT1 overexpression.
BackgroundVimentin is a member of the intermediate filament proteins and a canonical marker of the epithelial-mesenchymal transition (EMT), which is pivotal in tumorigenesis, metastasis and invasion in non-small cell lung cancer (NSCLC). The current meta-analysis aimed to investigate the associations between vimentin and prognosis and progression in NSCLC.MethodsDatabases with literature published in English, including PubMed, Web of Science, Embase, Science Direct, Wiley Online Library, Ovid, Cochrane Central Register of Controlled Trials, LILACS and Google Scholar, and the CNKI, VIP, CBM and WanFang databases in Chinese were used for the literature search. The key terms included (1) ‘vimentin’ OR ‘vim’ OR ‘vmt’ OR ‘vm’ OR ‘hel113’ OR ‘ctrct30’ and (2) ‘pulmon*’ OR ‘lung’ OR ‘alveolar’ and (3) ‘cancer’ OR ‘carcinoma’ OR ‘tumor’ OR ‘adenocarcinoma’ OR ‘squamous’ OR ‘neoplas*’ OR ‘malignan*’. The data were combined by random effect model and the H value and I2 were used to assess the heterogeneity. All the meta-analysis was conducted using Stata 12.0.ResultsThirty-two qualified studies (4118 cases) were included in the current meta-analysis. Twelve studies with 1750 patients were included to assess the significance of vimentin in the overall survival (OS) of NSCLC; the pooled hazard ratio (HR) was 1.831 (confidence interval (CI): 1.315–2.550, P<0.001) in the univariate analysis and 1.266 (CI: 0.906–1.768, P = 0.167) in the multivariate analysis. Four studies with 988 cases were applicable to determine the significance of vimentin in the disease-free survival (DFS) of NSCLC; the pooled HR of the DFS was 1.224 (CI: 0.921–1.628, P = 0.164) in the univariate analysis and 1.254 (CI: 0.985–1.956, P = 0.067) in the multivariate analysis. Regarding the relationships between vimentin and clinicopathological factors, the pooled odds ratio (OR) with 3406 NSCLCs indicated that up-regulated vimentin was associated with smoking (OR = 1.359, CI: 1.098–1.683, P = 0.004), poor differentiation (OR = 2.133, CI: 1.664–2.735, P<0.001), an advanced TNM stage (OR = 3.275, CI: 1.987–5.397, P<0.001), vascular invasion (OR = 3.492, CI: 1.063–11.472, P = 0.039), lymph node metastasis (OR = 2.628, CI: 1.857–3.718, P<0.001), recurrence (OR = 1.631, CI: 1.052–2.528, P = 0.029) and pleural invasion (OR = 2.346, CI: 1.397–3.941, P = 0.001). There was no significant correlation between vimentin and age, gender, diameter, T stage, distant metastasis, or marginal invasion (P>0.05).ConclusionAn overexpression of vimentin may predict the progression and an unfavorable survival of NSCLC. Vimentin may represent a helpful biomarker and a potential target for the treatment strategies of NSCLC. Additional, prospective studies with large samples are necessary to confirm the significance of vimentin in NSCLC.
Abstract. MicroRNAs (miRNAs) are short, non-proteincoding RNAs and transcripts that are 18-24 nt in length. miR-204 was first identified as an anti-oncogene and is reported to be downregulated in non-small cell lung cancer, glioma, gastric and thyroid cancer. Recent studies have proposed that a low level of miR-204 expression is associated with tumor progression and disease outcome in breast cancer. Forkhead box A1 (FOXA1), a transcription factor, plays a crucial role in breast cancer and has been predicted as a target of miR-204. In the present study, we integrated the results of microarray analyses of breast cancer tissues obtained from an online database with our own determination of the expression of miR-204 in breast cancer MCF-7 cells using real-time qPCR (RT-qPCR). The proliferative capacity of the cells was assessed using MTT assays, and cell mobility and invasiveness were evaluated using cell migration and invasion assays, respectively. Flow cytometry was used to analyze apoptosis. FOXA1 levels were detected using RT-qPCR and western blot analysis. Luciferase assays were performed to confirm that FOXA1 is directly targeted by miR-204. The results showed that miR-204 was downregulated in breast cancer cells, and we found that miR-204 was expressed at a lower level in MCF-7 cells than that observed in normal breast epithelial HBL-100 cells. Overexpression of miR-204 inhibited cell proliferation, migration and invasion and promoted apoptosis. Western blot analysis revealed that the expression of FOXA1 at the protein level was significantly reduced after cells were transfected with miR-204-expressing viruses. Luciferase assays demonstrated that FOXA1 is a direct target of miR-204, which binds to FOXA1 in a complementary region. In conclusion, miR-204 regulates the biological behavior of breast cancer cells, including cell proliferation, invasion, metastasis and apoptosis, by directly targeting FOXA1. Thus, miR-204 may act as a tumor-suppressor, and the results of the present study provide a reference for future research into the potential mechanisms underlying breast cancer progression.
Ki-67 is considered as one of prime biomarkers to reflect cell proliferation and immunohistochemical Ki-67 staining has been widely applied in clinical pathology. To solve the widespread controversy whether Ki-67 reactivity significantly predicts clinical prognosis of bladder carcinoma (BC), we performed a comprehensive meta-analysis by combining results from different literature.A comprehensive search was conducted in the Chinese databases of WanFang, China National Knowledge Infrastructure and Chinese VIP as well as English databases of PubMed, ISI web of science, EMBASE, Science Direct, and Wiley online library. Independent studies linking Ki-67 to cancer-specific survival (CSS), disease-free survival (DFS), overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS) were included in our meta-analysis. With the cut-off values literature provided, hazard ratio (HR) values between the survival distributions were extracted and later combined with STATA 12.0.In total, 76 studies (n = 13,053 patients) were eligible for the meta-analysis. It was indicated in either univariate or multivariate analysis for survival that high Ki-67 reactivity significantly predicted poor prognosis. In the univariate analysis, the combined HR for CSS, DFS, OS, PFS, and RFS were 2.588 (95% confidence interval [CI]: 1.623–4.127, P < 0.001), 2.697 (95%CI: 1.874–3.883, P < 0.001), 2.649 (95%CI: 1.632–4.300, P < 0.001), 3.506 (95%CI: 2.231–5.508, P < 0.001), and 1.792 (95%CI: 1.409–2.279, P < 0.001), respectively. The pooled HR of multivariate analysis for CSS, DFS, OS, PFS, and RFS were 1.868 (95%CI: 1.343–2.597, P < 0.001), 2.626 (95%CI: 2.089–3.301, P < 0.001), 1.104 (95%CI: 1.008–1.209, P = 0.032), 1.518 (95%CI: 1.299–1.773, P < 0.001), and 1.294 (95%CI: 1.203–1.392, P < 0.001), respectively. Subgroup analysis of univariate analysis by origin showed that Ki-67 reactivity significantly correlated with all 5 clinical outcome in Asian and European-American patients (P < 0.05). For multivariate analysis, however, the pooled results were only significant for DFS, OS, and RFS in Asian patients, for CSS, DFS, PFS, and RFS in European-American patients (P < 0.05). In the subgroup with low cut-off value (<20%), our meta-analysis indicated that high Ki-67 reactivity was significantly correlated with worsened CSS, DFS, OS, PFS, and RFS on univariate analysis (P < 0.05). For multivariate analysis, the meta-analysis of literature with low cut-off value (<20%) demonstrated that high Ki-67 reactivity predicted shorter DFS, PFS, and RFS in BC patients (P < 0.05). In the subgroup analysis of high cut-off value (≥20%), our meta-analysis indicated that high Ki-67 reactivity, in either univariate or multivariate analysis, significantly correlated with all five clinical outcomes in BC patients (P < 0.05).The meta-analysis indicates that high Ki-67 reactivity significantly correlates with deteriorated clinical outcomes in BC patients and that Ki-67 can be considered as an independent indicator for the prognosis by the me...
CCL18 was up-regulated in DLBCL and related to poor prognosis. CCL18 may act as a valuable target for diagnosis and treatment of DLBCL.
Introduction:Well-differentiated systemic mastocytosis (WDSM) is a rare, recently recognized provisional subvariant of systemic mastocytosis (SM). We report a case of WDSM that showed excellent clinical and cutaneous response to imatinib in the absence of known molecular genetic abnormalities.Clinical Findings/Diagnoses:We present a 24-year-old woman with childhood onset of skin manifestations that progressed to mediator-related systemic events, and a gastrointestinal tract mastocytoma. A subsequent bone marrow examination showed WDSM. Treatment with imatinib resulted in complete resolution of cutaneous lesions and systemic symptoms, which relapsed with the discontinuation of the drug. Targeted next-generation sequencing-based mutation analysis did not demonstrate any mutations in the coding regions of KIT or other genes commonly associated with myeloid neoplasms.Conclusions:The diagnosis of WDSM is challenging in the absence of spindle-shaped mast cells, CD2 or CD25 expression, and KIT D816 mutation. This case illustrated the need for recognizing this unique variant of SM for diagnostic and therapeutic implications.
Cyclin E is a critical regulator in cell cycle and promotes the initiation of DNA replication and centrosome duplication in late G1. The overexpression of cyclin E is common in cancers of the digestive system. However, whether cyclin E represents a prognostic biomarker in gastrointestinal cancer remains controversial. We reviewed the published literatures to clarify the association between cyclin E determined by immunohistochemistry (IHC) and survival in gastrointestinal cancer. Literatures were searched in PubMed and Cochrane Library published up to December 1, 2014. A total of 282 articles were initially identified, and 14 articles were included in this study. Meta-analysis was performed for 10 studies with a total of 1300 patients. Combined hazard risk (HR) and corresponding 95% confidence interval (CI) were calculated by random-effect model due to the heterogeneity. The quality of included studies was assessed by the Newcastle-Ottawa Scale and the Methodological Index for Non-Randomized Studies (MINORS). We found that high level of cyclin E was a predicator of poor prognosis among patients with gastrointestinal cancer (HR ¼ 1.67, 95% CI ¼ 1.06-2.63, P ¼ .028). In summary, overexpression of cyclin E is associated with poor prognosis in gastrointestinal cancer and expression of cyclin E determined by IHC might be a prognostic marker for gastrointestinal cancer in clinical practice.
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