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.
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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DOI：
10.1016/j.bbadis.2018.10.006
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Rhee SH
中科院分区：
文献类型：
--
作者：
Howe C;Kim SJ;Mitchell J;Im E;Kim YS;Kim YS;Rhee SH
磷酸酶和紧张素同源物（Pten）拮抗PI3K-Akt信号；因此，Pten损伤导致肿瘤发生。然而，由于许多相反的观察结果，Pten缺乏与结肠癌之间的相关性仍然难以捉摸。为了研究这种相关性，我们研究了肠上皮细胞（IECs）中Pten缺乏是否会诱导肿瘤发生。采用人结肠癌和正常结肠粘膜活检，定量PCR检测Pten mRNA的表达。使用iec特异性Pten敲除小鼠（PtenΔIEC/ΔIEC），我们检测了iec的有丝分裂活性；和PtenΔIEC /ΔIEC;将PtenΔIEC/ΔIEC与Apcmin/+小鼠组合生成Apcmin/+小鼠。微阵列分析肿瘤相关基因。通过16S rRNA基因测序分析粪便微生物组。我们发现Pten mRNA水平在人结肠癌中相对于正常组织有所降低。与Pten+/+窝鼠相比，PtenΔIEC/ΔIEC小鼠IECs染色单体增加，Ki-67和PCNA表达增加，Akt活化增强。PtenΔIEC/ΔIEC联合Apcmin/+可引起快速侵袭性肠道肿瘤发生。然而，PtenΔIEC/ΔIEC小鼠没有产生任何肿瘤。在保持肿瘤驱动潜能的同时，这些数据表明单独的IEC-Pten缺乏不会诱导小鼠的肿瘤发生。此外，与对照组相比，Pten ΔIEC/ΔIEC小鼠肠道中促肿瘤基因和抑肿瘤基因的表达分别减少和增加。与对照组相比，PtenΔIEC/ΔIEC小鼠中能够诱导慢性肠道炎症的嗜粘液阿克曼氏菌的丰度减少。这些发现表明，肿瘤相关基因表达的改变和肠道微生物形态的改变是肿瘤预防微环境，可以抵消肿瘤驱动潜能，从而导致PtenΔIEC/ΔIEC小鼠的肿瘤预防。
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 Pten ΔIEC/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 microbiotashape a tumor-preventive microenvironment to counteract the tumor-driving potential, leading to the tumor prevention in PtenΔIEC/ΔIEC mice.
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影响因子：
6
作者：
Balish, E;Warner, T
通讯作者：
Warner, T
影响因子：
3.5
作者：
Asano, A;Jin, HK;Watanabe, T
通讯作者：
Watanabe, T
DOI：
10.1126/science.1224820
发表时间：
2012-10-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Arthur JC;Perez-Chanona E;Mühlbauer M;Tomkovich S;Uronis JM;Fan TJ;Campbell BJ;Abujamel T;Dogan B;Rogers AB;Rhodes JM;Stintzi A;Simpson KW;Hansen JJ;Keku TO;Fodor AA;Jobin C
通讯作者：
Jobin C
影响因子：
4.4
作者：
Collado, M. Carmen;Derrien, Muriel;Isolauri, Erika
通讯作者：
Isolauri, Erika
影响因子：
3.7
作者：
Cronin JC;Loftus SK;Baxter LL;Swatkoski S;Gucek M;Pavan WJ
通讯作者：
Pavan WJ