Xiao Yunyun, Li Yue, Shi Dongni, Wang Xiaoqing, Dai Shuqin, Yang Muwen, Kong Lingzhi, Chen Boyu, Huang Xinjian, Lin Chuyong, Liao Wenting, Xu Benke, Chen Xin, Wang Lishuai, Chen Xiangfu, Ouyang Ying, Liu Guozhen, Li Heping, Song Libing
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Cancer Res. 2022 Nov 15;82(22):4191-4205. doi: 10.1158/0008-5472.CAN-22-1203.
Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)-mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3'UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC.
This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.
肿瘤转移是肝细胞癌（HCC）患者高死亡率的主要原因之一。STAT3信号的持续激活在HCC转移中起关键作用。RNA结合蛋白（RBP）介导的转录后调控参与信号转导的精确控制，包括STAT3信号。在本研究中，我们调查了RBP是否为HCC转移的重要调节因子。发现RBP MEX3C在高转移性HCC中显著上调，且与HCC的不良预后相关。机制上，MEX3C通过下调SOCS3（JAK2/STAT3信号的主要负调节因子）来增加JAK2/STAT3通路活性。MEX3C与SOCS3的3'UTR相互作用，并招募CNOT7使SOCS3 mRNA泛素化并加速其衰变。用MEX3C特异性反义寡核苷酸处理可显著抑制JAK2/STAT3通路激活，在体外抑制HCC迁移，在体内抑制转移。这些发现突出了一种新的mRNA衰变介导的机制，用于破坏SOCS3驱动的JAK2/STAT3信号负调控，表明MEX3C可能是HCC中一种潜在的预后生物标志物和有前景的治疗靶点。
本研究揭示RNA结合蛋白MEX3C诱导SOCS3 mRNA衰变以促进肝细胞癌中的JAK2/STAT3激活和肿瘤转移，确定靶向MEX3C是治疗转移性疾病的一种潜在方法。
