Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, PR China.
Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, PR China.
Exp Mol Med. 2024 May;56(5):1150-1163. doi: 10.1038/s12276-024-01223-0. Epub 2024 May 1.
Hepatocellular carcinoma (HCC) is associated with a poor prognosis. Our previous study demonstrated that Pleomorphic adenoma gene like-2 (PLAGL2) was a potential therapeutic target in HCC. However, the mechanisms that lead to the upregulation of PLAGL2 in HCC remain unclear. The present study revealed that stress-induced epinephrine increased the expression of PLAGL2, thereby promoting the progression of HCC. Furthermore, PLAGL2 knockdown inhibited epinephrine-induced HCC development. Mechanistically, epinephrine upregulated ubiquitin-specific protease 10 (USP10) to stabilize PLAGL2 via the adrenergic β-receptor-2-c-Myc (ADRB2-c-Myc) axis. Furthermore, PLAGL2 acted as a transcriptional regulator of USP10, forming a signaling loop. Taken together, these results reveal that stress-induced epinephrine activates the PLAGL2-USP10 signaling loop to enhance HCC progression. Furthermore, PLAGL2 plays a crucial role in psychological stress-mediated promotion of HCC progression.
肝细胞癌（HCC）预后不良。我们之前的研究表明，涎腺肿瘤基因样 2（PLAGL2）是 HCC 的一个潜在治疗靶点。然而，导致 HCC 中 PLAGL2 上调的机制尚不清楚。本研究揭示应激诱导的肾上腺素增加了 PLAGL2 的表达，从而促进了 HCC 的进展。此外，PLAGL2 敲低抑制了肾上腺素诱导的 HCC 发生。机制上，肾上腺素通过肾上腺素能β受体-2-c-Myc（ADRB2-c-Myc）轴上调泛素特异性蛋白酶 10（USP10）来稳定 PLAGL2。此外，PLAGL2 作为 USP10 的转录调节因子，形成信号环。总之，这些结果表明应激诱导的肾上腺素激活了 PLAGL2-USP10 信号环，从而增强了 HCC 的进展。此外，PLAGL2 在心理应激介导的 HCC 进展促进中起着关键作用。
Zotero 插件