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Gut dysbiosis with decreased Akkermansia muciniphila and differential expression of tumor‐associated genes contribute to a tumor‐preventive microenvironment in intestinal epithelial Pten‐deficient mice
Author(s) -
Rhee Sang Hoon,
Howe Cody,
Kim Su Jin,
Mitchell Jonathon,
Im Eunok
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.484.10
Subject(s) - pten , tensin , cancer research , carcinogenesis , biology , pi3k/akt/mtor pathway , tumor suppressor gene , colorectal cancer , cancer , signal transduction , microbiology and biotechnology , genetics
Phosphatase and tensin homolog (Pten) antagonizes PI3K‐Akt signaling; therefore, Pten impairment causes tumorigenesis. However, the correlation between Pten deficiency and colon cancer has remained elusive due to numerous opposite observations. To study this correlation, we examined whether Pten deficiency in intestinal epithelial cells (IECs) induces tumorigenesis. With mucosal biopsies of human colon cancer and normal colon, Pten mRNA was evaluated by quantitative PCR. Using IEC‐specific Pten knockout mice (Pten ΔIEC/ΔIEC ), we examined the mitotic activity of IECs; and Pten ΔIEC/ΔIEC ; Apc min/+ mice were generated by combining Pten ΔIEC/ΔIEC with Apc min/+ mice. Tumor‐associated gene was evaluated by micro‐array analysis. Fecal microbiome was analyzed through 16S rRNA gene sequencing. We found that Pten mRNA level was reduced in human colon cancer relative to normal tissues. Augmented chromatids, increased Ki‐67 and PCNA expression, and enhanced Akt activation were identified in IECs of Pten ΔIEC/ΔIEC mice compared to Pten +/+ littermate. Combining Pten ΔIEC/ΔIEC with Apc min/+ condition caused rapid and aggressive intestinal tumorigenesis. However, Pten ΔIEC/ΔIEC mice did not develop any tumors. While maintaining the tumor‐driving potential, these data indicated that IEC‐Pten deficiency alone did not induce tumorigenesis in mice. Furthermore, the expression of tumor‐promoting and tumor‐suppressing genes was decreased and increased, respectively, in the intestine of Pten ΔIEC/ΔIEC mice compared to controls. The abundance of Akkermansia muciniphila , capable of inducing chronic intestinal inflammation, was diminished in Pten ΔIEC/ΔIEC mice compared to controls. These findings suggested that altered tumor‐associated gene expression and changed gut microbiota shape a tumor‐preventive microenvironment to counteract the tumor‐driving potential, leading to the tumor prevention in Pten ΔIEC/ΔIEC mice. Support or Funding Information This research was supported by a grant from Oakland University and the National Institutes of Health (DK079015, S.H.R). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .