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Tumor-Associated Microbiota in Proximal and Distal Colorectal Cancer and Their Relationships With Clinical Outcomes.

ABSTRACT: The proximal and distal subsites of colorectal cancer (CRC) have distinct differences in their embryonic origin, epidemiology, and prognosis. Therefore, they are not considered as the same disease. However, the possible difference in microbial characterization of the two subsites of CRC is still unclear. In this study, we explored tumor microbiota diversity and composition difference in patients with proximal (N = 187) and distal CRCs (N = 142). This was carried out on cancer tissues and adjacent tissues using bacterial 16S rRNA sequencing. The Kaplan-Meier method was used to analyze the correlation between differential flora and overall survival rate of the patients. It was found that there were significant differences in tumor microbial characteristics between the proximal and distal CRC tissues. The microbiota communities were distinctly richer in the proximal colon tumor tissues than in the distal CRC tissues. Microbial diversity and structure were relatively constant in the paracancerous normal tissues of the proximal and distal colorectum. Generally, microbial communities of CRC tumor tissues were composed of Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Alpha diversity in the proximal and distal CRC tumor tissues was closely related to specific microflora. The abundance of Fusobacteria was associated with age of patient, tumor diameter, and tumor microsatellite instability (MSI) status of the patients. Moreover, Fusobacteria enrichment was associated with poor prognosis especially in patients with proximal colon cancers, but not in patients with distal CRC. In conclusion, proximal and distal subsites of the CRC present distinct microbiota diversity and community structures. The differences indicate that there are different risk factors across anatomical subsites of CRC, which may provide a new strategy for precise prevention and treatment of CRC in the future.

SUBMITTER: Jin M

PROVIDER: S-EPMC8506159 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Many genes are regulated by two or more enhancers that drive similar expression patterns. Evolutionary theory suggests that these seemingly redundant enhancers must have functionally important differences. In the simple ascidian chordate Ciona, the transcription factor Brachyury is induced exclusively in the presumptive notochord downstream of lineage specific regulators and FGF-responsive Ets family transcription factors. Here we exploit the ability to finely titrate FGF signaling activity via the MAPK pathway using the MEK inhibitor U0126 to quantify the dependence of transcription driven by different Brachyury reporter constructs on this direct upstream regulator. We find that the more powerful promoter-adjacent proximal enhancer and a weaker distal enhancer have fundamentally different dose-response relationships to MAPK inhibition. The Distal enhancer is more sensitive to MAPK inhibition but shows a less cooperative response, whereas the Proximal enhancer is less sensitive and more cooperative. A longer construct containing both enhancers has a complex dose-response curve that supports the idea that the proximal and distal enhancers are moderately super-additive. We show that the overall expression loss from intermediate doses of U0126 is not only a function of the fraction of cells expressing these reporters, but also involves graded decreases in expression at the single-cell level. Expression of the endogenous gene shows a comparable dose-response relationship to the full length reporter, and we find that different notochord founder cells are differentially sensitive to MAPK inhibition. Together, these results indicate that although the two Brachyury enhancers have qualitatively similar expression patterns, they respond to FGF in quantitatively different ways and act together to drive high levels of Brachyury expression with a characteristic input/output relationship. This indicates that they are fundamentally not equivalent genetic elements.

Dataset Information

Tumor-Associated Microbiota in Proximal and Distal Colorectal Cancer and Their Relationships With Clinical Outcomes.

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