State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
Department of Clinical Oncology, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
Cell Death Dis. 2021 Jan 26;12(1):125. doi: 10.1038/s41419-021-03422-3.
Hepatocellular carcinoma (HCC) is one of the common malignancy and lacks effective therapeutic targets. Here, we demonstrated that ectopic expression of trophinin-associated protein (TROAP) dramatically drove HCC cell growth assessed by foci formation in monolayer culture, colony formation in soft agar and orthotopic liver transplantation in nude mice. Inversely, silencing TROAP expression with short-hairpin RNA attenuated the malignant proliferation of HCC cells in vitro and in vivo. Next, mechanistic investigation revealed that TROAP directly bound to dual specificity tyrosine phosphorylation regulated kinase 1A/B (DYRK1A/B), resulting in the cytoplasmic retention of proteins DYRK1A/B and promoting cell cycle process via activation of Akt/GSK-3β signaling. Combination of cisplatin with an inhibitor of DYRK1 AZ191 effectively inhibited tumor growth in mouse model for HCC cells with high level of TROAP. Clinically, TROAP was significantly upregulated by miR-142-5p in HCC tissues, which predicted the poor survival of patients with HCC. Therefore, TROAP/DYRK1/Akt axis may be a promising therapeutic target and prognostic indicator for patients with HCC.
肝细胞癌 (HCC) 是一种常见的恶性肿瘤，缺乏有效的治疗靶点。在这里，我们证明了外源性表达滋养蛋白相关蛋白 (TROAP) 通过单层培养中的焦点形成、软琼脂中的集落形成以及裸鼠原位肝移植显著驱动 HCC 细胞生长。相反，用短发夹 RNA 沉默 TROAP 表达可减弱 HCC 细胞在体外和体内的恶性增殖。接下来，机制研究表明 TROAP 可直接与双特异性酪氨酸磷酸化调节激酶 1A/B (DYRK1A/B) 结合，导致 DYRK1A/B 蛋白的细胞质滞留，并通过激活 Akt/GSK-3β 信号通路促进细胞周期进程。顺铂与 DYRK1A 的抑制剂 AZ191 的联合使用可有效抑制高 TROAP 水平的 HCC 细胞在小鼠模型中的肿瘤生长。临床上，TROAP 在 HCC 组织中被 miR-142-5p 显著上调，这预示着 HCC 患者的生存不良。因此，TROAP/DYRK1/Akt 轴可能是 HCC 患者有前途的治疗靶点和预后指标。
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