PUMP 蛋白通过抑制 p21 促进结直肠癌生长。

PUMILIO proteins promote colorectal cancer growth via suppressing p21.

机构信息

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.

出版信息

Nat Commun. 2022 Mar 25;13(1):1627. doi: 10.1038/s41467-022-29309-1.

PUMILIO (PUM) proteins belong to the highly conserved PUF family post-transcriptional regulators involved in diverse biological processes. However, their function in carcinogenesis remains under-explored. Here, we report that Pum1 and Pum2 display increased expression in human colorectal cancer (CRC). Intestine-specific knockout of Pum1 and Pum2 in mice significantly inhibits the progression of colitis-associated cancer in the AOM/DSS model. Knockout or knockdown of Pum1 and/or Pum2 in human CRC cells result in a significant decrease in the tumorigenicity and delayed G1/S transition. We identify p21/Cdkn1a as a direct target of PUM1. Abrogation of the PUM1 binding site in the p21 mRNA also results in decreased cancer cell growth and delayed G1/S transition. Furthermore, intravenous injection of nanoparticle-encapsulated anti-Pum1 and Pum2 siRNAs reduces colorectal tumor growth in murine orthotopic colon cancer models. These findings reveal the requirement of PUM proteins for CRC progression and their potential as therapeutic targets.

PUMILIO（PUM）蛋白属于高度保守的 PUF 家族转录后调控因子，参与多种生物学过程。然而，它们在癌症发生中的作用仍未得到充分探索。在这里，我们报告 Pum1 和 Pum2 在人结直肠癌（CRC）中表达增加。在小鼠中特异性敲除 Pum1 和 Pum2 可显著抑制 AOM/DSS 模型中结肠炎相关癌症的进展。敲除或敲低人 CRC 细胞中的 Pum1 和/或 Pum2 可导致肿瘤发生能力显著降低，G1/S 期转换延迟。我们确定 p21/Cdkn1a 是 PUM1 的直接靶标。p21 mRNA 中 PUM1 结合位点的缺失也会导致癌细胞生长减少和 G1/S 期转换延迟。此外，静脉注射纳米颗粒包封的抗 Pum1 和 Pum2 siRNAs 可减少小鼠原位结直肠癌模型中的结直肠肿瘤生长。这些发现揭示了 PUM 蛋白在 CRC 进展中的必要性及其作为治疗靶点的潜力。