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Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2

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 sign...

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Autores principales: Xie, Meng, Sun, Mengyu, Ji, Xiaoyu, Li, Dongxiao, Chen, Xiaoping, Zhang, Bixiang, Huang, Wenjie, Zhang, Tongyue, Wang, Yijun, Tian, Dean, Xia, Limin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8771560/
https://www.ncbi.nlm.nih.gov/pubmed/35154476
http://dx.doi.org/10.7150/thno.65775
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author Xie, Meng
Sun, Mengyu
Ji, Xiaoyu
Li, Dongxiao
Chen, Xiaoping
Zhang, Bixiang
Huang, Wenjie
Zhang, Tongyue
Wang, Yijun
Tian, Dean
Xia, Limin
author_facet Xie, Meng
Sun, Mengyu
Ji, Xiaoyu
Li, Dongxiao
Chen, Xiaoping
Zhang, Bixiang
Huang, Wenjie
Zhang, Tongyue
Wang, Yijun
Tian, Dean
Xia, Limin
author_sort Xie, Meng
collection PubMed
description 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.
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spelling pubmed-87715602022-02-10 Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2 Xie, Meng Sun, Mengyu Ji, Xiaoyu Li, Dongxiao Chen, Xiaoping Zhang, Bixiang Huang, Wenjie Zhang, Tongyue Wang, Yijun Tian, Dean Xia, Limin Theranostics Research Paper 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. Ivyspring International Publisher 2022-01-01 /pmc/articles/PMC8771560/ /pubmed/35154476 http://dx.doi.org/10.7150/thno.65775 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Xie, Meng
Sun, Mengyu
Ji, Xiaoyu
Li, Dongxiao
Chen, Xiaoping
Zhang, Bixiang
Huang, Wenjie
Zhang, Tongyue
Wang, Yijun
Tian, Dean
Xia, Limin
Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2
title Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2
title_full Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2
title_fullStr Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2
title_full_unstemmed Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2
title_short Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2
title_sort overexpression of bach1 mediated by igf2 facilitates hepatocellular carcinoma growth and metastasis via igf1r and ptk2
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8771560/
https://www.ncbi.nlm.nih.gov/pubmed/35154476
http://dx.doi.org/10.7150/thno.65775
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