BackgroundGiven the emerging role of microRNA in tumor disease progression, we investigated the association between microRNA expression, liver metastasis and prognosis of colorectal cancer.MethodsColorectal cancer tissues from patients with or without liver metastases were profiled to identify differentially expressed microRNA. Expression profile was further assessed using quantitative reverse transcription PCR and in situ hybridization. Correlation between miR-181a expression, the most differentially expressed microRNA, between patients with and without liver metastasis, and its downstream target genes were investigated using qRT-PCR. Luciferase reporter assay was conducted to establish functional association between miR-181a and its target genes. Manipulation of miR-181a expression and its consequences in tumor growth and metastasis were demonstrated in various in vitro and in vivo models.ResultsmiR-181a was revealed being the most elevated in CRC with liver metastases. miR-181a expression correlated with advanced stage, distant metastasis, and served as an independent prognostic factor of poor overall survival. Stable transfection of CRC cell lines with miR-181a promoted cell motility and invasion, as well as tumor growth and liver metastasis,while silencing its expression resulted in reduced migration and invasion. Additionally, we identified WIF-1 as direct and functional targets of miR-181a. Ectopic expression of miR-181a suppressed the epithelial markers E-cadherin and β-catenin, while enhanced the mesenchymal markers vimentin.ConclusionOur data demonstrate that miR-181a expression is associated with CRC liver metastasis and survival. miR-181a has strong tumor-promoting effects through inhibiting the expression of WIF-1, and its potential role in promoting epithelial-mesenchymal transition.

SummaryChemo-/radiotherapy resistance is the main cause accounting for most treatment failure in colorectal cancer (CRC). Tumor-initiating cells (TICs) are the culprit leading to CRC chemo-/radiotherapy resistance. The underlying regulation mechanism of TICs in CRC remains unclear. Here we discovered that miR-15b expression positively correlated with therapeutic outcome in CRC. Expression of miR-15b in pretreatment biopsy tissue samples predicted tumor regression grade (TRG) in rectal cancer patients after receiving neoadjuvant radiotherapy (nRT). Expression of miR-15b in post-nRT tissue samples was associated with therapeutic outcome. DCLK1 was identified as the direct target gene for miR-15b and its suppression was associated with self-renewal and tumorigenic properties of DCLK1+ TICs. We identified B lymphoma Mo-MLV insertion region l homolog (BMI1) as a downstream target regulated by miR-15b/DCLK1 signaling. Thus, miR-15b may serve as a valuable marker for prognosis and therapeutic outcome prediction. DCLK1 could be a potential therapeutic target to overcome chemo-/radioresistance in CRC.

This study was designed to develop novel and better reliable serum prognostic biomarkers for colorectal cancer (CRC). A 50 sample set including CRC, adenoma and healthy control sera was used to identify the serum proteins involved in CRC carcinogenesis using serum proteomic approach. Alpha-2-glycoprotein 1, zinc-binding (AZGP1), pigment epithelium derived factor (PEDF) and peroxiredoxin 2 (PRDX2) were selected as good candidates. Two independent cohorts of 868 individuals were enrolled. The expression of selected proteins in serum from cohort 1 (n = 534) was quantified with enzyme-linked immunosorbent assays. CRC sera of this cohort (n = 405) were assigned to training and test sets, which were used to identify and verify the prognostic markers. The prognostic values of identified proteins were further validated in cohort 2 (n = 334) using quantitative reverse transcription PCR and immunohistochemical staining. Our data showed that the elevated AZGP1 and decreased PEDF and PRDX2 expressions in CRC serum and tissues were correlated with liver metastases. In the training set, higher AZGP1 and lower PEDF levels in sera were significantly associated with a poorer overall survival (OS), higher AZGP1 was also associated with a poorer disease-free survival (DFS). This association was verified in the testing set and further validated in patients in cohort 2. Patients with lower PEDF or PRDX2 levels in their CRC tissues had a significantly poorer DFS or OS than patients with high levels of these proteins in cohort 2. Univariate and multivariate analyses indicated that the prognostic performance of serum AZGP1 and PEDF was independent of other clinicopathological factors. We propose that they may serve as prognostic markers and potential therapeutic targets in CRC.

BackgroundCarcinoembryonic antigen (CEA) is a glycoprotein associated with colorectal cancer (CRC). While the functions of its gene and protein have been fully characterized, its post-translational modifications in the context of CRC development remain undefined.MethodsTo show the correlation between the different stages of CRC development and changes in the glycosylation patterns of CEA, we analyzed CEA in tumor tissues (CEA-T) and paired tumor-adjacent normal tissues (CEA-A) from 53 colorectal cancer patients using a high-density lectin microarray containing 56 plant lectins.ResultsWe detected higher expression levels of fucose, mannose and Thomsen–Friedenreich antigen, and lower expression levels of N-acetylgalactosamine, N-acetylglucosamine, galactose, branched and bisecting N-glycans on CEA in the tumor tissues relative to the tumor-adjacent normal tissues. Furthermore, a combinatorial assessment of 9 lectins is sufficient to distinguish CRC tumor tissues from tumor-adjacent normal tissues with 83% sensitivity and ~ 90% specificity. Moreover, the levels of N-acetylgalactosamine, mannose, galactose, N-acetylglucosamine on CEA showed a downward trend after first experiencing an increase at Stage II with the stages of CRC.ConclusionsOur insights into the changing CEA glycosylation patterns and their role in the development of CRC highlight the importance of glycan variants on CEA for early clinical detection and staging of CRC.Electronic supplementary materialThe online version of this article (10.1186/s12014-018-9182-4) contains supplementary material, which is available to authorized users.