Table_1_RET is a sex-biased regulator of intestinal tumorigenesis.xlsx

Ret is implicated in colorectal cancer (CRC) as both a proto-oncogene and a tumor suppressor. We asked whether RET signaling regulates tumorigenesis in an Apc-deficient preclinical model of CRC. We observed a sex-biased phenotype: ApcMin/+Ret+/- females had significantly greater tumor burden than ApcMin/+Ret+/- males, a phenomenon not seen in ApcMin/+ mice, which had equal distributions by sex. Dysfunctional RET signaling was associated with gene expression changes in diverse tumor signaling pathways in tumors and normal-appearing colon. Sex-biased gene expression differences mirroring tumor phenotypes were seen in 26 genes, including the Apc tumor suppressor gene. Ret and Tlr4 expression were significantly correlated in tumor samples from female but not male ApcMin/+Ret+/- mice. Antibiotics resulted in reduction of tumor burden, inverting the sex-biased phenotype such that microbiota-depleted ApcMin/+Ret+/- males had significantly more tumors than female littermates. Reconstitution of the microbiome rescued the sex-biased phenotype. Our findings suggest that RET represents a sexually dimorphic microbiome-mediated “switch” for regulation of tumorigenesis.

RET基因在结直肠癌（CRC）中既作为原癌基因又作为肿瘤抑制基因发挥作用。本研究旨在探讨RET信号通路是否在APC基因缺陷的结直肠癌前期动物模型中调节肿瘤发生。研究发现存在性别偏倚的表型：与ApcMin/+Ret+/-雄性小鼠相比，ApcMin/+Ret+/-雌性小鼠的肿瘤负荷显著增加，而在ApcMin/+小鼠中并未观察到这种现象，其性别分布均等。肿瘤及外观正常的结肠中，异常的RET信号通路与多种肿瘤信号通路中的基因表达改变相关。在26个基因中观察到与肿瘤表型相对应的性别偏倚的基因表达差异，包括Apc肿瘤抑制基因。在雌性而非雄性ApcMin/+Ret+/-小鼠的肿瘤样本中，Ret和Tlr4的表达显著相关。抗生素的使用导致肿瘤负荷减少，逆转了性别偏倚的表型，使得菌群耗竭的ApcMin/+Ret+/-雄性小鼠的肿瘤数量显著多于雌性同胞。微生物组的重建挽救了性别偏倚的表型。我们的研究结果表明，RET代表了一种性二态的菌群介导的“开关”，该开关调节肿瘤发生。