T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1
T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1
复制标题
T-box转录因子19通过上调EGFR和RAC1促进肝细胞癌转移
DOI：
10.1038/s41388-022-02249-2
复制
发表时间：
2022-02-26
期刊：
影响因子：
8
通讯作者：
Xia，Limin
中科院分区：
文献类型：
--
作者：
Ji，Xiaoyu;Chen，Xiaoping;Xia，Limin
转移性肝细胞癌（HCC）的靶向治疗效果仍不理想。探索HCC转移的潜在机制有助于提供新的治疗策略。T-box （TBX）转录因子家族基因是胚胎和器官发育的重要调控因子，对肿瘤的发生、生长和转移起着至关重要的作用。TBX19是人类肝癌组织中表达上调最多的TBX家族基因之一，我们探讨了TBX19在肝癌转移中的作用。TBX19在HCC组织中表达明显上调，TBX19表达升高预示预后不良。TBX19过表达通过上调表皮生长因子受体（EGFR）和Rac家族小GTPase 1 （RAC1）表达而增强HCC转移。EGFR和RAC1下调可抑制TBX19介导的肝癌转移，而EGFR和RAC1上调可恢复TBX19敲低介导的肝癌转移抑制。此外，表皮生长因子(EGF)/EGFR信号通路通过细胞外信号调节激酶(ERK)/核因子(NF)-kB轴上调TBX19的表达。此外，EGFR抑制剂厄洛替尼与RAC1抑制剂NSC23766联合应用可显著抑制tbx19介导的HCC转移。在HCC队列中，TBX19表达与EGFR和RAC1表达呈正相关。TBX19/EGFR或TBX19/RAC1共表达阳性的患者预后最差。综上所述，EGF/EGFR信号通路通过ERK/NF-kB途径上调TBX19表达，TBX19通过增强EGFR和RAC1表达促进HCC转移，形成EGF-TBX19-EGFR正反馈回路。靶向这一信号通路可能为有效抑制tbx19介导的HCC转移提供潜在的治疗策略。
The effect of targeted therapy for metastatic hepatocellular carcinoma (HCC) is still unsatisfactory. Exploring the underlying mechanism of HCC metastasis is favorable to provide new therapeutic strategies. T-box (TBX) transcription factor family genes, which are crucial regulators in embryo and organ development, are vital for regulating tumor initiation, growth and metastasis. Here we explored the role of TBX19 in HCC metastasis, which is one of the most upregulated TBX family genes in human HCC tissues. TBX19 expression was markedly upregulated in HCC tissues and elevated TBX19 expression predicted poor prognosis. Overexpression of TBX19 enhanced HCC metastasis through upregulating epidermal growth factor receptor (EGFR) and Rac family small GTPase 1 (RAC1) expression. Downregulation of EGFR and RAC1 inhibited TBX19-mediated HCC metastasis, while upregulation of EGFR and RAC1 restored inhibition of HCC metastasis mediated by TBX19 knockdown. Furthermore, epidermal growth factor (EGF)/EGFR signaling upregulated TBX19 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor (NF)-kB axis. Besides, the combined application of EGFR inhibitor Erlotinib and RAC1 inhibitor NSC23766 markedly inhibited TBX19-mediated HCC metastasis. In HCC cohorts, TBX19 expression was positively associated with EGFR and RAC1 expression. Patients with positive coexpression of TBX19/EGFR or TBX19/RAC1 displayed the poorest prognosis. In conclusion, EGF/EGFR signaling upregulated TBX19 expression via ERK/NF-kB pathway and TBX19 fostered HCC metastasis by enhancing EGFR and RAC1 expression, which formed an EGF-TBX19-EGFR positive feedback loop. Targeting this signaling pathway may offer a potential therapeutic strategy to efficiently restrain TBX19-mediated HCC metastasis.