The role of Snail and serpin peptidase inhibitor clade A member 1 (serpinA1) in tumorigenesis has been previously identified. However, the exact role and mechanism of these proteins in progression of colorectal cancer (CRC) are controversial. In this study, we investigated the role of Snail and serpinA1 in colorectal cancer (CRC) and examined the mechanisms through which these proteins mediate CRC progression. Immunohistochemical analysis of 528 samples from patients with CRC showed that elevated expression of Snail or serpinA1 was correlated with advanced stage, lymph node metastasis, and poor prognosis. Moreover, we detected a correlation between Snail and serpinA1 expression. Functional studies performed using the CRC cell lines DLD-1 and SW-480 showed that overexpression of Snail or serpinA1 significantly increased CRC cell invasion and migration. Conversely, knockdown of Snail or serpinA1 expression suppressed CRC cell invasion and migration. ChIP analysis revealed that Snail regulated serpinA1 by binding to its promoter. In addition, fibronectin mediated Snail and serpinA1 signaling was involved in CRC cell invasion and migration. Taken together, our data showed that Snail and serpinA1 promoted CRC progression through fibronectin. These findings suggested that Snail and serpinA1 were novel prognostic biomarkers and candidate therapeutic targets in CRC.

BackgroundDespite the clinical significance of liver metastases, the difference between molecular and cellular changes in primary colorectal cancers (CRC) and matched liver metastases is poorly understood.MethodsIn order to compare gene expression patterns and identify fusion genes in these two types of tumors, we performed high-throughput transcriptome sequencing of five sets of quadruple-matched tissues (primary CRC, liver metastases, normal colon, and liver).ResultsThe gene expression patterns in normal colon and liver were successfully distinguished from those in CRCs; however, RNA sequencing revealed that the gene expression between primary CRCs and their matched liver metastases is highly similar. We identified 1895 genes that were differentially expressed in the primary carcinoma and liver metastases, than that in the normal colon tissues. A major proportion of the transcripts, identified by gene expression profiling as significantly enriched in the primary carcinoma and metastases, belonged to gene ontology categories involved in the cell cycle, mitosis, and cell division. Furthermore, we identified gene fusion events in primary carcinoma and metastases, and the fusion transcripts were experimentally confirmed. Among these, a chimeric transcript resulting from the fusion of RNF43 and SUPT4H1 was found to occur frequently in primary colorectal carcinoma. In addition, knockdown of the expression of this RNF43-SUPT4H1 chimeric transcript was found to have a growth-inhibitory effect in colorectal cancer cells.ConclusionsThe present study reports a high concordance of gene expression in the primary carcinoma and liver metastases, and reveals potential new targets, such as fusion genes, against primary and metastatic colorectal carcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2596-3) contains supplementary material, which is available to authorized users.

The identification and clinical validation of cancer driver genes are essential to accelerate the translational transition of cancer genomics, as well as to find clinically confident targets for the therapeutic intervention of cancers. Here we identified recurrent LMNA-NTRK1 and TPM3-NTRK1 fusions in Korean patients with colon cancer (3 out of 147, 2%) through next-generation RNA sequencing (RNA-seq). NTRK1 fusions were mutually exclusive oncogenic drivers of colon cancer that were accompanied with in vitro potential of colony formation and in vivo tumorigenicity comparable to KM12, a human colon cancer cell line harboring TPM3-NTRK1 fusion. NTRK1-encoded TrkA protein was prevalent in 11 out of 216 Korean (5.1%) and 28 out of 472 Chinese patients (5.9%) from independent cohorts, respectively. The expression level of TrkA was significantly correlated with NTRK1 fusion (p = 0.0192), which was verified by a fluorescence in situ hybridization (FISH). Korean patients with TrkA-positive colon cancer had a marginal but significant shorter overall survival time than TrkA-negative colon cancer [hazard ratio (HR) = 0.5346, 95% confidential interval (CI) = 0.2548-0.9722, p = 0.0411]. In addition, KM12 cell line was sensitive to selective TrkA inhibitors. These results demonstrate that NTRK1 fusion is granted as a clinically relevant target for therapeutic intervention of colon cancer.

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BackgroundIntersphincteric resection (ISR) has become an increasingly popular optional surgical tool for the treatment of very low rectal cancer. The purpose of this study was to assess the long-term oncological and functional outcomes of intersphincteric resection for T2 and T3 rectal cancer situated below 4 cm from the anal verge.MethodsA total of 62 consecutive patients with very low rectal cancer who underwent ISR from 2001 to 2010 were classified into standard ISR for T2 lesions (Group I, n = 24) and extended ISR for T3 lesions (Group II, n = 38).ResultsThe 5-year overall survival rates were 95.8 % for group I and 94.7 % for group II. The 5-year recurrence-free survival rates were 87.5 % for group I and 86.8 % for group II. Bowel functions were evaluated at the 12th and 24th months after ileostomy closure in both groups. The frequency of bowel evacuation was higher in patients who underwent extended ISR than in those who underwent standard ISR at the 12th month (p < 0.05). However, at the 24th month, the frequencies decreased in both groups, exhibiting no significant difference. In the comparison based on the Kirwan classification, group I showed better continence status than group II but no significant difference. The Wexner scores of both groups revealed that the average score was 7.33 ± 2.8 in group I and 8.18 ± 2.9 in group II at the 12th month, and at the 24th month, the average score was 5.21 ± 1.7 in group I and 5.82 ± 1.9 in group II. There were no statistically significant differences between the two groups.ConclusionsExtended ISR with quadrant resection of the upper external sphincter achieved good post-operative continence status, OS and RFS. Extended ISR can thus be an alternative to abdominoperineal resection for very low rectal cancer without compromising the chance of cure and improving quality of life.