CD44是一种与癌症进展有关的细胞外基质受体。CD44增加了皮肤（SF）和子宫内膜基质成纤维细胞（ESF）对癌细胞和滋养层细胞的侵袭能力。我们推测，CD44表达的演化可能会影响胎儿-母体相互作用，通过ESF中的CD44，以及通过SF中的表达对恶性癌症的易感性。我们研究了哺乳动物SF和ESF中CD44表达的演化，并证明人类系进化出较高的CD44表达。牛和人类的异构体表达非常相似，表明侵袭性差异不是由于表达的异构体性质而引起的。然后，我们询问了共同基因表达在两种细胞类型中是否由于共享的调控机制或由于细胞类型特异性因素而增加。利用人类和牛细胞及其顺式调控元件进行的报告基因实验表明，CD44表达的差异是由于顺式效应和细胞类型特异性转移效应造成的。这些结果表明，协调的表达增加很可能是因为选择作用在两种细胞类型上发挥作用，因为细胞类型特异性因素的演化变化需要对细胞类型特异性功能的选择。这种情况暗示，在人类中升高的CD44表达的恶性增强效应很可能是CD44的其他功能的阳性选择的副作用。一个可能的候选者是CD44的抗纤维化作用，但没有可靠的数据显示人类和灵长类动物不如其他哺乳动物纤维化。©作者2022。由牛津大学出版社代表演化、医学和公共卫生基金会出版。

CD44 is an extracellular matrix receptor implicated in cancer progression. CD44 increases the invasibility of skin (SF) and endometrial stromal fibroblasts (ESF) by cancer and trophoblast cells. We reasoned that the evolution of CD44 expression can affect both, the fetal-maternal interaction through CD44 in ESF as well as vulnerability to malignant cancer through expression in SF. We studied the evolution of CD44 expression in mammalian SF and ESF and demonstrate that in the human lineage evolved higher CD44 expression. Isoform expression in cattle and human is very similar suggesting that differences in invasibility are not due to the nature of expressed isoforms. We then asked whether the concerted gene expression increase in both cell types is due to shared regulatory mechanisms or due to cell type-specific factors. Reporter gene experiments with cells and cis-regulatory elements from human and cattle show that the difference of CD44 expression is due to cis effects as well as cell type-specific trans effects. These results suggest that the concerted expression increase is likely due to selection acting on both cell types because the evolutionary change in cell type-specific factors requires selection on cell type-specific functions. This scenario implies that the malignancy enhancing effects of elevated CD44 expression in humans likely evolved as a side-effect of positive selection on a yet unidentified other function of CD44. A possible candidate is the anti-fibrotic effect of CD44 but there are no reliable data showing that humans and primates are less fibrotic than other mammals.© The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.