Abstract
Colorectal cancer (CRC) is one of the most common cancers in humans and a leading cause of cancer-related deaths worldwide. As in the case of other cancers, CRC heterogeneity leads to a wide range of clinical outcomes and complicates therapy. Over the years, multiple factors have emerged as markers of CRC heterogeneity, improving tumor classification and selection of therapeutic strategies. Understanding the molecular mechanisms underlying this heterogeneity remains a major challenge. A considerable research effort is therefore devoted to identifying additional features of colorectal tumors, in order to better understand CRC etiology and to multiply therapeutic avenues. Recently, long noncoding RNAs (lncRNAs) have emerged as important players in physiological and pathological processes, including CRC. Here we looked for lncRNAs that might contribute to the various colorectal tumor phenotypes. We thus monitored the expression of 4898 lncRNA genes across 566 CRC samples and identified 282 lncRNAs reflecting CRC heterogeneity. We then inferred potential functions of these lncRNAs. Our results highlight lncRNAs that may participate in the major processes altered in distinct CRC cases, such as WNT/β-catenin and TGF-β signaling, immunity, the epithelial-to-mesenchymal transition (EMT), and angiogenesis. For several candidates, we provide experimental evidence supporting our functional predictions that they may be involved in the cell cycle or the EMT. Overall, our work identifies lncRNAs associated with key CRC characteristics and provides insights into their respective functions. Our findings constitute a further step towards understanding the contribution of lncRNAs to CRC heterogeneity. They may open new therapeutic opportunities.
Highlights
According to the latest statistics, colorectal cancer is the third most common cancer in men worldwide (746,000 cases, representing 10% of all cases) and the second in women (614,000 cases, 9.2% of all cases) [1]
We focused on tumor location, CpG Island Methylator Phenotype status (CIMP positive or negative), Mismatch Repair (MMR) machinery status, and Chromosome Instability status (CIN high or chromosome instability (CIN) low), as associations have been evidenced between these features and Colorectal cancer (CRC) subtypes based on mRNA [12] and long noncoding RNAs (lncRNAs) [24] profiles
We selected the GSE39582 dataset for the following reasons: (i) it is, to our knowledge, the largest cohort (n = 566) of colorectal tumor samples with gene expression profiles (GEPs) data arising from the same study; (ii) each tumor has been assigned to a robust mRNA-based CRC subtype, and (iii) the dataset contains extensive clinical information, including relapse-free survival data (Figure 1A and Supplementary Table 1)
Summary
According to the latest statistics, colorectal cancer is the third most common cancer in men worldwide (746,000 cases, representing 10% of all cases) and the second in women (614,000 cases, 9.2% of all cases) [1]. A variety of molecular features have helped clinicians to better classify various types of colorectal tumors and scientists to better understand the molecular defects causing colorectal adenomas and carcinomas [3,4,5] Such characteristics can be associated with prognosis and/or response to treatment and have been used to identify CRC subtypes [4, 6, 7]. The main focus of this quest has been on gene expression profiles (GEPs) These have been used, along with the above-mentioned molecular features, to distinguish up to six distinct CRC subtype [5, 10,11,12]. Their findings help to explain the divergent fates of molecularly similar cases, as tumors with distinct GEPs may share similar molecular characteristics [12]
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