Differential expression of tumor-associated genes and altered gut microbiome with decreased Akkermansia muciniphila confer a tumor-preventive microenvironment in intestinal epithelial Pten-deficient mice |
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Authors: | Cody Howe Su Jin Kim Jonathon Mitchell Eunok Im Yong Sung Kim You Sun Kim Sang Hoon Rhee |
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Institution: | 1. Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA;2. College of Pharmacy, Pusan National University, Busan, Republic of Korea;3. Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;4. Gastroenterology, Wonkwang University Sanbon Hospital, Wonkwang Digestive Disease Research Institute, Gunpo, Gyeonggi-do 435-040, Republic of Korea;5. Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine, Seoul 100-032, Republic of Korea |
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Abstract: | 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 (PtenΔIEC/ΔIEC), we examined the mitotic activity of IECs; and PtenΔIEC/ΔIEC; Apcmin/+ mice were generated by combining PtenΔIEC/ΔIEC with Apcmin/+ 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 PtenΔIEC/ΔIEC mice compared to Pten+/+ littermate. Combining PtenΔIEC/ΔIEC with Apcmin/+ condition caused rapid and aggressive intestinal tumorigenesis. However, PtenΔIEC/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 PtenΔIEC/ΔIEC mice compared to controls. The abundance of Akkermansia muciniphila, capable of inducing chronic intestinal inflammation, was diminished in PtenΔIEC/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 PtenΔIEC/ΔIEC mice. |
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Keywords: | Apaf1 apoptotic peptidase activating factor 1 Casp7 caspase-7 Ccnd2 Cyclin D2 Cdc20 cell division cycle 20 homolog IEC intestinal epithelial cells Kdr kinase insert domain receptor Pten phosphatase and tensin homolog Mcm2 minichromosome maintenance protein 2 Mal MyD88 adaptor-like PCNA proliferating cell nuclear antigen Sox10 SRY-box 10 Tirap TIR domain–containing adaptor protein TLR5 Toll-like receptor 5 Microbiome Pten Toll-like receptor Tumor microenvironment Tumor prevention |
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