RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.

RNA 结合蛋白 (RBP)-RNA 网络有助于癌症的发展。环状 RNA (circRNA) 被认为是蛋白质招募者；然而，结直肠癌（CRC）中 circRNA-蛋白质相互作用的模式仍然缺乏。通过液-液相分离（LLPS）形成的加工体（PB）是由RBP和RNA组成的无膜细胞器（MLO）。先前的证据表明 PB 动态与癌症进展之间存在联系。尽管人们越来越认识到 RBP 和 RNA 在 MLO 积累和维持中的关键作用，但仍然缺乏关于 CRC 中 PBs 相关 RBP 和 circRNA 之间相互作用的具体研究。在此，我们发现 MEX-3 RNA 结合家族成员 A (MEX3A) 在 CRC 组织中经常上调，预测患者生存率较差。 MEX3A 升高会加速恶性肿瘤并抑制 CRC 细胞的自噬。重要的是，MEX3A 在细胞质中经历本质上无序区域 (IDR) 依赖性 LLPS。具体来说，circMPP6 作为支架促进 MEX3A 和 PBs 蛋白之间的相互作用。 MEX3A/circMPP6 复合物调节 PB 动态并促进 UPF 介导的磷酸二酯酶 5A ( PDE5A ) mRNA 降解，从而导致 CRC 细胞的侵袭性。临床上，MEX3A高表达和PDE5A低表达的CRC患者的总生存期最差。我们的研究结果揭示了 MEX3A 和 circMPP6 之间通过触发 PB 聚集来调节 mRNA 衰减的合作，这为 CRC 提供了预后标记和/或治疗靶点。