Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei, 430030, China.
Theranostics. 2022 Jan 1;12(3):1097-1116. doi: 10.7150/thno.65775. eCollection 2022.
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. 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 and 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 () and protein tyrosine kinase 2 () by BACH1. 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 and . 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. 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.
越来越多的研究表明，BTB 和 CNC 同源结构域 1（BACH1）促进多种恶性肿瘤的进展和转移，靶向 BACH1 通路可增强抗肿瘤疗效。然而，BACH1 促进生长和转移的确切机制及其在肝细胞癌（HCC）中的治疗意义仍不清楚。通过定量 RT-PCR（RT-qPCR）、western blot 和免疫组织化学（IHC）分析人 HCC 标本和 HCC 细胞系中 BACH1 的表达。使用 Transwell 测定和原位异种移植模型评估 HCC 细胞的侵袭和转移。进行荧光素酶报告基因测定和染色质免疫沉淀（ChIP）测定，以探讨 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。BACH1 在人 HCC 样本中明显上调，BACH1 表达升高与 HCC 患者总生存率（OS）降低和复发率升高相关。BACH1 通过上调细胞运动相关基因和来促进 HCC 的生长和转移。值得注意的是，胰岛素样生长因子 2（IGF2）是 IGF1R 的配体，通过 IGF1R-ERK1/2-ETS1 级联反应反过来上调 BACH1 的表达，从而形成正反馈环，引发 HCC 的生长和转移。此外，结合 IGF1R 抑制剂 linsitinib 和 PTK2 抑制剂 defactinib 可显著抑制 BACH1 介导的 HCC 生长和转移。这些结果表明 BACH1 在 HCC 中具有致癌和促转移作用，可作为预测不良预后和选择可能受益于 IGF1R 靶向和 PTK2 定向联合治疗的患者的有前途的生物标志物。
