Evolutionary biologic changes of gut microbiota in an 'adenoma-carcinoma sequence' mouse colorectal cancer model induced by 1, 2-Dimethylhydrazine.

Teng Sun,Zhiliang Wei,Shanglong Liu,Dongfeng Zhang,Bin Tan,Song Wang,Zengwu Yao,Yanbing Zhou,Yi Li,Shougen Cao,Zheng Lian

doi:10.18632/oncotarget.13443

Abstract

The molecular biological mechanisms underlying the evolutionary biologic changes leading to carcinogenesis remain unclear. The main objective of our study was to explore the evolution of the microbiota community and molecules related with CRC in the dynamic transition from normal colon epithelium to premalignant adenoma with the aid of an ‘adenoma–carcinoma sequence’ mouse CRC model induced by DMH. We generated a modified mouse CRC model induced by DMH for DNA sequences, and characterized the molecular networks. Data from 454 pyrosequencing of the V3- V5 region of the 16S rDNA gene and immunohistochemical detection of APC, P53, K-RAS and BRAF genes were assessed with Principal coordinates, UniFrac, and Kruskal-Wallis rank sum test. The inflammatory group showed enrichment of Bacteroidetes and Porphyromonadaceae (P < 0.01). OTUs affiliated with Firmicutes were enriched in the hyperproliferative group (P < 0.01). Rikenellaceae and Ruminococcaceae showed an increasing trend during the CRC process while the opposite pattern was observed for Prevotellaceaeand Enterobacteriaceae. OTUs related to Alistipes finegoldii were significantly increased during CRC development, P53, K-RAS and BRAF, were gradually increased (P < 0.05). Conversely, expression of APC was decreased during the course of development of CRC. Our results demonstrate that the biological evolutionary shift of gut microbiota, characterized by a gradual decrease in ‘driver’ bacteria and an increase in DNA damage-causing bacteria, is accompanied by tumor development in the CRC model. The synergistic actions of microbiota dysbiosis and effects of bacterial metabolites on related molecular events are proposed to contribute to the progression of CRC tumorigenesis.

Highlights

Colorectal cancer is the third most common cancer type in men and the second most common in women, and reported as the fourth leading cause of cancer-related mortality worldwide [1, 2]
The main objective of our study was to explore the evolution of the microbiota community and molecules related with CRC in the dynamic transition from normal colon epithelium to premalignant adenoma with the aid of an ‘adenoma–carcinoma sequence’ mouse CRC model induced by DMH
Our results demonstrate that the biological evolutionary shift of gut microbiota, characterized by a gradual decrease in ‘driver’ bacteria and an increase in DNA damage-causing bacteria, is accompanied by tumor development in the CRC model

Summary

Introduction

Colorectal cancer is the third most common cancer type in men and the second most common in women, and reported as the fourth leading cause of cancer-related mortality worldwide [1, 2]. The most commonly mutated genes include tumor suppressors (APC, P53 and www.impactjournals.com/oncotarget the β-catenin gene) and oncogenes (K-RAS, BRAF and MYC). The triggers for these mutations are multifactorial in origin, associated with infectious agents and high exposure of tissues to microbiota, but remain elusive in many cases [6]. From this perspective, Tjalsmaet et al [7] proposed a bacterial driver-passenger model explaining microbiota community involvement during CRC development, which may contribute to the genetic paradigm of the ‘adenomacarcinoma sequence’. Existing bacteria may enhance the susceptibility to disease, such as Helicobacter pylori to gastric cancer and human papilloma virus to cervical cancer

Objectives

Methods

Results

Conclusion