Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2.
Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2.
复制标题
IGF2介导的BACH1过表达通过IGF1R和PTK2促进肝细胞癌生长和转移
作者：
Xie M;Sun M;Ji X;Li D;Chen X;Zhang B;Huang W;Zhang T;Wang Y;Tian D;Xia L
背景：越来越多的研究表明，BTB和CNC同源物1 （BACH1）促进了多种恶性肿瘤的进展和转移，靶向BACH1通路可提高抗肿瘤疗效。然而，BACH1促进肝细胞癌（HCC）生长和转移的确切机制及其治疗意义尚不清楚。方法：采用定量RT-PCR （RT-qPCR）、免疫印迹（western blot）和免疫组化（IHC）技术分析BACH1在人肝癌标本和肝癌细胞系中的表达。采用transwell法和原位异种移植模型评估肝癌细胞在体外和体内的侵袭性和转移。采用荧光素酶报告基因法和染色质免疫沉淀法（ChIP）研究BACH1对胰岛素样生长因子1受体（IGF1R）和蛋白酪氨酸激酶2 （PTK2）的转录调控作用。结果：BACH1在人类HCC样本中显著上调，BACH1表达升高与HCC患者总生存率低（OS）和复发率高相关。BACH1通过上调细胞运动相关基因IGF1R和PTK2促进HCC的生长和转移。值得注意的是，IGF1R的配体胰岛素样生长因子2 （IGF2）反过来通过IGF1R- erk1 /2- ets1级联上调BACH1的表达，从而形成一个正反馈回路，刺激HCC的生长和转移。此外，IGF1R抑制剂linsitinib联合PTK2抑制剂defactinib显著抑制bach1介导的HCC生长和转移。结论：这些结果证明了BACH1在HCC中的致瘤性和促转移作用，它可能是一个有希望的生物标志物，用于预测预后不良和选择可以从igf1r靶向和ptk2靶向联合治疗中获益的患者。
Background: Accumulating studies manifest that BTB and CNC homology 1 (BACH1) facilitates multiple malignancies progression and metastasis, and targeting the BACH1 pathway enhances antitumor efficacy. Nevertheless, the exact mechanism of BACH1 promoting growth and metastasis and its therapeutic significance in hepatocellular carcinoma (HCC) remain unclear. Methods: The expression of BACH1 in human HCC specimens and HCC cell lines was analyzed by quantitative RT-PCR (RT-qPCR), western blot, and immunohistochemistry (IHC). The invasiveness and metastasis of HCC cells in vitro and in vivo were evaluated using transwell assays and orthotopic xenograft models. The luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were performed to explore the transcriptional regulation of insulin-like growth factor 1 receptor (IGF1R) and protein tyrosine kinase 2 (PTK2) by BACH1. Results: BACH1 was prominently upregulated in human HCC samples and elevated BACH1 expression was associated with poor overall survival (OS) and high recurrence rates of HCC patients. BACH1 facilitated growth and metastasis of HCC by upregulating cell motility-related genes IGF1R and PTK2. Notably, insulin-like growth factor 2 (IGF2), the ligand of IGF1R, in turn upregulated BACH1 expression through the IGF1R-ERK1/2-ETS1 cascades, thus forming a positive feedback loop to provoke HCC growth and metastasis. Moreover, combining IGF1R inhibitor linsitinib with PTK2 inhibitor defactinib prominently suppressed BACH1-mediated HCC growth and metastasis. Conclusions: These results demonstrated the tumorigenic and pro-metastatic role of BACH1 in HCC, which could be a promising biomarker for predicting poor prognosis and selecting patients who could benefit from combination therapy of IGF1R-targeted and PTK2-directed.