Abstract
BackgroundGiven the differences in embryonic origin, vascular and nervous supplies, microbiotic burden, and main physiological functions of left and right colons, tumor location is increasingly suggested to dictate tumor behavior affecting pathology, progression and prognosis. Right-sided colon cancers arise in the cecum, ascending colon, hepatic flexure and/or transverse colon, while left-sided colon cancers arise in the splenic flexure, descending, and/or sigmoid colon. In contrast to prior reports, we attempt to delineate programs of tumorigenesis independently for each side.MethodsFour hundred and eleven samples were extracted from The Cancer Genome Atlas-COAD cohort, based on a conservative sample inclusion criterion. Each side was independently analyzed with respect to their respective normal tissue, at the level of transcription, post-transcription, miRNA control and methylation in both a stage specific and stage-agnostic manner.ResultsOur results indicate a suppression of enzymes involved in various stages of carcinogen breakdown including CYP2C8, CYP4F12, GSTA1, and UGT1A within right colon tumors. This implies its reduced capacity to detoxify carcinogens, contributing to a genotoxic tumor environment, and subsequently a more aggressive phenotype. Additionally, we highlight a crucial nexus between calcium homeostasis (sensing, mobilization and absorption) and immune/GPCR signaling within left-sided tumors, possibly contributing to its reduced proliferative and metastatic potential. Interestingly, two genes SLC6A4 and HOXB13 show opposing regulatory trends within right and left tumors. Post-transcriptional regulation mediated by both RNA-binding proteins (e.g. NKRF (in left) and MSI2 (in right)) and miRNAs (e.g. miR-29a (in left); miR-155, miR181-d, miR-576 and miR23a (in right)) appear to exhibit side-specificity in control of their target transcripts and is pronounced in right colon tumors. Additionally, methylation results depict location-specific differences, with increased hypomethylation in open seas within left tumors, and increased hypermethylation of CpG islands within right tumors.ConclusionsDifferences in molecular mechanisms captured here highlight distinctions in tumorigenesis and progression between left and right colon tumors, which will serve as the basis for future studies, influencing the efficacies of existing and future diagnostic, prognostic and therapeutic interventions.
Highlights
Given the differences in embryonic origin, vascular and nervous supplies, microbiotic burden, and main physiological functions of left and right colons, tumor location is increasingly suggested to dictate tumor behavior affecting pathology, progression and prognosis
Establishing transcriptional regulation in RSCC and LSCC Differential analysis identified 2495 Differentially expressed genes (DEGs) in LSCC, with respect to left normal colon tissue, and 2589 DEGs in RSCC, with respect to right normal colon tissue (Fig. 1a). 957 and 975 DEGs are identified to be commonly regulated in both RSCC and LSCC while, 655 and 561 DEGs are “uniquely” regulated in RSCC and LSCC, respectively (Fig. 1b and c)
A common program of tumorigenesis exists between right and left sided colon tumors Malignant tumor cells are highly plastic and are characterized by alterations in metabolism, adhesion, proliferation and migration, requiring coordinated activity of several signaling pathways and mechanisms
Summary
Given the differences in embryonic origin, vascular and nervous supplies, microbiotic burden, and main physiological functions of left and right colons, tumor location is increasingly suggested to dictate tumor behavior affecting pathology, progression and prognosis. Colorectal cancer (CRC) is a heterogeneous disease with distinct clinical, molecular, and pathophysiological characteristics. Location of tumor within the colon is gaining traction as crucial factor in determining disease progression, prognosis and management, and begs the question if colon and rectal cancers can be treated as being mechanistically similar [3]. To this extent we focus our attention on discerning the molecular mechanisms governing colon cancer, tumors arising in the left and right colons
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