Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou 310016, China.
Proc Natl Acad Sci U S A. 2023 Jul 25;120(30):e2220296120. doi: 10.1073/pnas.2220296120. Epub 2023 Jul 17.
Metastasis, especially intrahepatic, is a major challenge for hepatocellular carcinoma (HCC) treatment. Cytoskeleton remodeling has been identified as a vital process mediating intrahepatic spreading. Previously, we reported that HCC tumor adhesion and invasion were modulated by circular RNA (circRNA), which has emerged as an important regulator of various cellular processes and has been implicated in cancer progression. Here, we uncovered a nuclear circRNA, circASH2, which is preferentially lost in HCC tissues and inhibits HCC metastasis by altering tumor cytoskeleton structure. Tropomyosin 4 (TPM4), a critical binding protein of actin, turned out to be the major target of circASH2 and was posttranscriptionally suppressed. Such regulation is based on messenger RNA (mRNA)/precursormRNA splicing and degradation process. Furthermore, liquid-liquid phase separation of nuclear Y-box binding protein 1 (YBX1) enhanced by circASH2 augments TPM4 transcripts decay. Together, our data have revealed a tumor-suppressive circRNA and, more importantly, uncovered a fine regulation mechanism for HCC progression.
转移，特别是肝内转移，是肝细胞癌 (HCC) 治疗的主要挑战。细胞骨架重塑已被确定为介导肝内扩散的重要过程。先前，我们报道了环状 RNA (circRNA) 调节 HCC 肿瘤黏附和侵袭，它作为各种细胞过程的重要调节剂，并且与癌症进展有关。在这里，我们发现了一种核 circRNA，circASH2，它在 HCC 组织中优先丢失，并通过改变肿瘤细胞骨架结构抑制 HCC 转移。肌球蛋白 4 (TPM4) 是肌动蛋白的关键结合蛋白，结果被 circASH2 作为主要靶点并被转录后抑制。这种调节基于信使 RNA (mRNA)/前体 mRNA 剪接和降解过程。此外，circASH2 增强的核 Y 盒结合蛋白 1 (YBX1) 的液-液相分离增强了 TPM4 转录本的降解。总之，我们的数据揭示了一种肿瘤抑制性的 circRNA，更重要的是，揭示了 HCC 进展的精细调控机制。
