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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2022
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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. |
format | Online Article Text |
id | pubmed-8771560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
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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