Abstract
Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.
Highlights
Occurrence of distant metastases is the main cause of sporadic colorectal cancer death, and the liver is the most common site for metastatic spread of the primary tumor [1, 2]
Both the primary tumors and their paired liver metastases showed overexpression of FOXQ1, MMP7, CLDN1 and TACSTD2 mRNAS and the miR-4417, miR-503, miR-1290, miR-3687, miR-183, miR-224 and miR-1246 miRNAs, together with downregulated levels of the CLCA4, CA1, AQP8, ZG16, GUCA2B and SLC26A3 mRNAS and the miR-215, miR-133a, miR-375, miR-133b and miR-138 miRNAs. Most of these genes with highly deregulated expression in both primary tumors and their corresponding liver metastases have been previously found to be altered/ involved in colorectal cancer (e.g., FOXQ1, MMP7, TACSTD2 CLCA4, CA1, AQP8, ZG16, GUCA2B and SLC26A3) and/or they have been identified as genes that are relevant to the metastatic process (e.g., FOXQ1, MMP7, TACSTD2 CLCA4, CA1, AQP8 and SLC26A3); the miRNAs, miR-503, miR-3687, miR-215, miR-133a, miR-375, miR-183, miR-1290, miR-224, miR-1246, have been reported to be typically altered in CRC
Despite the similarities observed between the gene expression profiling (GEP) of primary and metastatic tumors, some transcripts were found to be deregulated in liver metastases while expressed at normal levels in their paired primary tumors, reflecting either an increased genomic instability of metastatic cells or their adaption to the liver microenvironment (Table 3)
Summary
Occurrence of distant metastases is the main cause of sporadic colorectal cancer (sCRC) death, and the liver is the most common site for metastatic spread of the primary tumor [1, 2]. Genomic abnormalities www.impactjournals.com/oncotarget which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. This relates to the fact that most genomic studies performed in colorectal cancer have focused on primary tumors, in stage II disease, at diagnosis; in contrast, few studies have compared the deregulated transcripts of primary versus paired metastatic samples. Multiple mRNAs and miRNAS found to be expressed in primary tumors have been associated with metastatic colorectal carcinoma. These include mRNA of PTEN/PI3K [5], EGFR [6], TGFβ [7], and TP53 [8], as well as the metastatic CRC-associated miRNAs, miR-31 [9], miR-503 [10] and miR-133a [11]
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