Functional Genomics Laboratory, Institut Pasteur Montevideo, Montevideo, Uruguay.
Analytical Biochemistry Unit, Nuclear Research Center, Faculty of Science, Universidad de la República, Montevideo, Uruguay.
Sci Rep. 2024 Oct 13;14(1):23928. doi: 10.1038/s41598-024-75098-6.
PIWI proteins, traditionally associated with germline development, have recently gained attention for their expression in various cancers, including colorectal cancer. However, the molecular mechanisms underlying their reactivation and impact on cancer initiation and progression remain elusive. Here, we found that PIWIL1 is expressed at relatively high levels in CRC-derived samples and cell lines, where it undergoes a dynamic relocalization to the centrosome during mitosis. Knockdown of PIWIL1 induces G2/M arrest associated with disruption of the mitotic spindle and aberrant metaphase events, highlighting its role in cell cycle progression. We also found that the expression of PIWIL1 is lost during the differentiation of Caco-2 cells into enterocytes and that PIWIL1 is expressed in cells at the base of the intestinal crypts in normal human colon tissue, where intestinal stem cells are known to reside. Thus, it is possible that the presence of PIWIL1 in cancer cells reflects a physiological role of this protein in stem cell maintenance, which would argue in favor of the proposed stem cell origin of CRC. Supporting this view, dedifferentiation of human fibroblasts into induced pluripotent stem cells (iPSCs) involves the reactivation of PIWIL2 expression, another member of the PIWI protein family. Overall, our findings suggest a role of PIWIL1 in mediating cell cycle dynamics, both in colorectal cancer cells and possibly also in intestinal stem cells. In a broader aspect, we provide evidence supporting an involvement of PIWI proteins in somatic stem cell maintenance, thus expanding the known non-gonadal functions of this protein family.
PIWI 蛋白传统上与生殖系发育有关，最近因其在包括结直肠癌在内的各种癌症中的表达而受到关注。然而，其重新激活的分子机制及其对癌症起始和进展的影响仍不清楚。在这里，我们发现 PIWIL1 在 CRC 来源的样本和细胞系中表达水平相对较高，在有丝分裂过程中它经历动态重定位到中心体。PIWIL1 的敲低诱导 G2/M 期阻滞，伴有有丝分裂纺锤体的破坏和异常中期事件，突出了其在细胞周期进展中的作用。我们还发现，PIWIL1 的表达在 Caco-2 细胞分化为肠上皮细胞的过程中丢失，并且在正常人类结肠组织中肠隐窝底部的细胞中表达 PIWIL1，已知肠道干细胞就位于此处。因此，癌细胞中 PIWIL1 的存在可能反映了该蛋白在干细胞维持中的生理作用，这将支持 CRC 起源于干细胞的假说。支持这一观点的是，人成纤维细胞分化为诱导多能干细胞 (iPSC) 涉及 PIWIL2 表达的重新激活，PIWIL2 是 PIWI 蛋白家族的另一个成员。总的来说，我们的研究结果表明 PIWIL1 在调节结直肠癌细胞和可能的肠道干细胞的细胞周期动力学中起作用。在更广泛的方面，我们提供了证据支持 PIWI 蛋白参与体干细胞维持，从而扩展了该蛋白家族已知的非性腺功能。
