Journal of Experimental & Clinical Cancer Research (2017) 36:78
ANGPTL1 attenuates colorectal cancer metastasis by up-regulating microRNA-138
Expression data for ANGPTL1 in CRC and additional cancer types were extracted from level 3 TCGA RNA-seq data, totaling 705 paired tumor and normal samples. To determine the key differentially regulated genes between paired cancer and normal tissues, we compared gene expression profiles between cancer and normal groups by DEGSeq package for R/Bioconductor, and the P value was adjusted according to the false discovery rate. In addition, the relationship between the ANGPTL1 expression and its clinical manifestations was validated by publicly available independent microarray datasets (GSE32323 and GSE24550).Furthermore, the GSE29623 and GSE35982 datasets, with information on both mRNA and microRNA (miRNA), were used to identify differentially expressed miRNA between high-ANGPTL1 and low-ANGPTL1 groups. All expression profiling data in this study were downloaded from TCGA (http://cancergenome.nih.gov/) and the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/). We were able to use these databases by meeting the freedom-to-publish criteria of TCGA and NCBI.To identify genes of tumorigenic potential, we analyzed gene expression profiles of paired cancerous and normal tissues from TCGA datasets. Gene expression analyses revealed that ANGPTL1, ANGPTL5 and ANGPTL7 were significantly down-regulated in CRC samples (Fig. 1a). Among them, ANGPTL1 was most significantly changed, and, remarkably, it was down-regulated in 87.5% (14/16) of cancer types, including breast invasive carcinoma, lung adenocarcinoma and thyroid carcinoma (Table 1). Apart from ANGPTL1, most ANGPTLs were also dramatically down-regulated in tumor tissues compared to the corresponding normal samples (Additional file 1: Table S1). Next, we validated our finding in the GSE32323 cohort from the GEO database. Analysis of 17 paired CRC and normal samples showed that ANGPTL1 was down-regulated in tumor samples (P = 0.01) (Fig. 1b). Finally, we confirmed these results in our oncology center. The basic characteristics of these patients are specified in Additional file 2: Table S2. Unsurprisingly, the results were similar to what we had found in TCGA and GEO datasets (P = 0.02, Fig. 1c). The low expression of ANGPTL1 in CRC and many other cancer types suggested that it was a potential suppressor of cancer and may be associated with CRC initiation and progression.To further determine the clinical significance of ANGPTL1 expression, we explored its association with survival information in TCGA dataset. The results showed that patients with high ANGPTL1 mRNA level had significantly longer OS than patients with low level of ANGPTL1 in stage IV metastatic CRC (P = 0.03, Fig. 1d). Moreover, in the GSE24550 cohort, high expression of ANGPTL1 predicted better disease-free survival in stage III patients (P = 0.03, Fig. 1e). Taken together, these results suggested that high ANGPTL1 expression was correlated with better survival in CRC patients.Not applicable.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0548-7) contains supplementary material, which is available to authorized users.