Table_2_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）的发生发展中扮演着既为原癌基因又为肿瘤抑制因子的双重角色。本研究旨在探究RET信号通路是否调控了APC基因缺陷型结直肠癌的肿瘤发生。研究发现，存在性别差异的表型：与ApcMin/+Ret+/-雄鼠相比，ApcMin/+Ret+/-雌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，其性别分布均衡。肿瘤及正常外观结肠中，功能失调的RET信号通路与多种肿瘤信号通路中的基因表达改变相关。在包括APC肿瘤抑制基因在内的26个基因中，观察到与肿瘤表型相似的性别偏向基因表达差异。在雌性ApcMin/+Ret+/-小鼠的肿瘤样本中，Ret和Tlr4的表达显著相关，而在雄性小鼠中则未观察到。抗生素的使用导致肿瘤负荷减少，逆转了性别偏向的表型，使得微生物群耗竭的ApcMin/+Ret+/-雄鼠的肿瘤数量显著多于雌性同胞。微生物群的重建挽救了性别偏向的表型。本研究结果表明，RET可能代表着一种性二态性的、由微生物群介导的肿瘤发生调控‘开关’。