Background: CD44 is widely used as a putative cancer stem cells (CSCs) marker for colorectal cancer (CRC). However, the prognostic role of CD44 in CRC remains controversial. Methods: We performed a systematic review and meta-analysis to evaluate the association of various CD44 isoforms and overall survival (OS) and clinicopathological features of CRC patients. Results: A total of 48 studies were included in the meta-analysis. Total CD44 isoforms overexpression was significantly correlated with worse OS of patients with CRC (HR = 1.32, 95% CI = 1.08–1.61, P = 0.007). In a stratified analysis, a higher level of either CD44v6 or CD44v2 had an unfavorable impact on OS (HR CD44v6 = 1.50, 95% CI = 1.10–2.14, P = 0.010; HR CD44v2 = 2.93, 95% CI = 1.49–5.77, P = 0.002). Additionally, CD44 was shown to be associated with some clinicopathological features, such as lymph node metastasis (OR CD44 = 1.56, 95% CI = 1.01–2.41, P = 0.044; OR CD44v6 = 1.97, 95% CI = 1.19–3.26, P = 0.008; OR Total CD44 isoforms = 1.57, 95% CI = 1.15–2.14, P = 0.004), distant metastasis (OR CD44 = 2.90, 95% CI = 1.08–7.83, P = 0.035; OR Total CD44 isoforms = 1.89, 95% CI = 1.02–3.53, P = 0.044). Moreover, a high level of CD44 showed a possible correlation with poor differentiation (OR Total CD44 isoforms = 1.44, 95% CI = 1.00–2.08, P = 0.051), elevated level of CD44v6 tend to be correlated with tumor size (OR = 1.71, 95% CI = 0.99–2.96, P = 0.056). Conclusions: This meta-analysis demonstrated that CD44 overexpression might be an unfavorable prognostic factor for CRC patients and could be used to predict poor differentiation, lymph node metastasis and distant metastasis.
Vasculogenic mimicry (VM) plays an important role in colorectal cancer (CRC) metastasis, and both hypoxia and the epithelial-mesenchymal transition (EMT) are necessary for VM. In this study, HIF-1α expression was upregulated in the VM-positive CRC cell line HCT-116 and thereby affected the expression of the EMT-related markers Claudin-4, E-cadherin (E-cd) and Vimentin(VIM). SB431542 and U0126EtOH, which can inhibit of EMT were used to treat HCT-116 and HCT-8 in these experiments. Both of the inhibitors had significant effect on EMT markers and the formations of VM in CRC cells. In addition, knockdown of HIF-1α in the HCT-116 cells inhibited their capacity for VM. Our study reveals a regulatory role for HIF-1α in VM and suggests that targeting either HIF-1α or EMT may be a valuable strategy for the elimination of CRC metastasis.
BackgroundIncreasing studies showed that abnormal changes in single nucleotide polymorphisms (SNPs) of DNMTs (DNMT1, DNMT3A and DNMT3B) were associated with occurrence or decrease of various tumors. However, the associations between DNMTs variations and gastric cancer (GC) risk were still conflicting. We aimed to assess the effect of DNMTs polymorphisms on the susceptibility to GC.MethodsFirstly, we did a meta-analysis for 7 SNPs (rs16999593, rs2228611, rs8101866 in DNMT1, rs1550117, rs13420827 in DNMT3A, rs1569686, rs2424913 in DNMT3B). Four genetic models (homozygote, heterozygote, dominant and recessive model) were used. Moreover, a meta-sensitivity and subgroup analysis was performed to clarify heterogeneity source. Lastly, 17 SNPs that couldn't be meta-analyzed were presented in a systematic review.Findings20 studies were included, 13 studies could be meta-analyzed and 7 ones could not. Firstly, a meta-analysis on 13 studies (3959 GC cases and 5992 controls) for 7 SNPs showed that GC risk increased in rs16999593 (heterozygote model: OR 1.36, 95%CI 1.14–1.61; dominant model: OR 1.36, 95%CI 1.15–1.60) and rs1550117 (homozygote model: OR 2.03, 95%CI 1.38–3.00; dominant model: OR 1.20, 95%CI 1.01–1.42; recessive model: OR 1.96, 95%CI 1.33–2.89) but decreased in rs1569686 (dominant model: OR 0.74, 95%CI 0.61–0.90). The remaining SNPs were not found associated with GC risk. Furthermore, the subgroup analysis indicated that for rs1550117 and rs1569686, the significant associations were particularly found in people from Chinese Jiangsu province (rs1550117, OR 1.77, 95%CI 1.25–2.51; rs1569686, OR 0.48, 95%CI 0.36–0.64) and that PCR-RFLP was a sensitive method to discover significant associations (rs1550117, OR 1.77, 95%CI 1.25–2.51; rs1569686, OR 0.49, 95%CI 0.37–0.65). Lastly, a systematic review on 7 studies for 17 SNPs suggested that rs36012910, rs7560488 and rs6087990 might have a potential effect on GC initiation.ConclusionThis meta-analysis demonstrated that rs16999593 and rs1550117 could contribute to GC risk and that rs1569686 might be a protective factor against gastric carcinogenesis. By using these SNPs as biomarkers, it is feasible to estimate the risk of acquiring GC and thus formulate timely preventive strategy.
BackgroundCancer stem cell (CSC) epithelial cell adhesion molecule (Ep-CAM) is frequently expressed in colorectal cancer (CRC). However, the clinical significance of Ep-CAM expression in CRC is not clear. This study evaluated whether Ep-CAM provided valuable insight as a molecular biomarker for CRC diagnosis and prognosis and the potential of Ep-CAM as a novel therapeutic target in CRC.MethodsPublications were selected online using electronic databases. The pooled odds ratios (ORs) or hazard ratios (HRs) with their 95% confidence intervals (95% CIs), and the combined sensitivity, specificity, and area under the curve (AUC) were calculated and summarized.ResultsEleven eligible articles published in English involving 4561 cases were analyzed in this study. Ep-CAM expression was significantly higher in CRC compared with normal controls, and its overexpression was negatively linked to tumor differentiation, tumor stage, vascular invasion, depth of tumor invasion, lymph node metastasis, distant metastasis, and tumor budding in CRC patients. The loss of Ep-CAM expression positively correlated with these characteristics. Multivariate analysis of loss of Ep-CAM expression correlated with a poor prognosis in disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). The pooled sensitivity, specificity and AUC values of Ep-CAM expression in patients with CRC vs. normal controls were 0.93, 0.90, and 0.94, respectively.ConclusionsThe present findings suggest that Ep-CAM expression may be associated with CRC carcinogenesis, while the loss of Ep-CAM expression is correlated with the progression, metastasis, and poor prognosis of CRC. Ep-CAM expression may be a useful biomarker for the clinical diagnosis of CRC.
MicroRNAs (miRNAs) are a class of small noncoding RNA molecules containing only 20–22 nucleotides. MiRNAs play a role in gene silencing and translation suppression by targeting and binding to mRNA. Proper control of miRNA expression is very important for maintaining a normal physiological environment because miRNAs can affect most cellular pathways, including cell cycle checkpoint, cell proliferation, and apoptosis pathways, and have a wide range of target genes. With these properties, miRNAs can modulate multiple signalling pathways involved in cancer development, such as cell proliferation, apoptosis, and migration pathways. MiRNAs that activate or inhibit the molecular pathway related to tumour angiogenesis are common topics of research. Angiogenesis promotes tumorigenesis and metastasis by providing oxygen and diffusible nutrients and releasing proangiogenic factors and is one of the hallmarks of tumour progression. CRC is one of the most common tumours, and metastasis has always been a difficult issue in its treatment. Although comprehensive treatments, such as surgery, radiotherapy, chemotherapy, and targeted therapy, have prolonged the survival of CRC patients, the overall response is not optimistic. Therefore, there is an urgent need to find new therapeutic targets to improve CRC treatment. In a series of recent reports, miRNAs have been shown to bidirectionally regulate angiogenesis in colorectal cancer. Many miRNAs can directly act on VEGF or inhibit angiogenesis through other pathways (HIF-1a, PI3K/AKT, etc.), while some miRNAs, specifically many exosomal miRNAs, are capable of promoting CRC angiogenesis. Understanding the mechanism of action of miRNAs in angiogenesis is of great significance for finding new targets for the treatment of tumour angiogenesis. Deciphering the exact role of specific miRNAs in angiogenesis is a challenge due to the high complexity of their actions. Here, we describe the latest advances in the understanding of miRNAs and their corresponding targets that play a role in CRC angiogenesis and discuss possible miRNA-based therapeutic strategies.
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