Cargando…

HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2

Background: Metastasis is a major cause of HCC-related deaths with no effective pharmacotherapies. Chronic inflammation promotes HCC dissemination, however, its underlying mechanisms are not fully understood. Here, we investigated the role of Krüppel-like factor 7 (KLF7) in inflammation-provoked HCC...

Descripción completa

Detalles Bibliográficos
Autores principales: Feng, Weibo, Chen, Jie, Huang, Wenjie, Wang, Guodong, Chen, Xilang, Duan, Lili, Yin, Yue, Chen, Xiaoping, Zhang, Bixiang, Sun, Mengyu, Luo, Xiangyuan, Nie, Yongzhan, Fan, Daiming, Wu, Kaichun, Xia, Limin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405848/
https://www.ncbi.nlm.nih.gov/pubmed/37554278
http://dx.doi.org/10.7150/thno.84388
_version_ 1785085624217239552
author Feng, Weibo
Chen, Jie
Huang, Wenjie
Wang, Guodong
Chen, Xilang
Duan, Lili
Yin, Yue
Chen, Xiaoping
Zhang, Bixiang
Sun, Mengyu
Luo, Xiangyuan
Nie, Yongzhan
Fan, Daiming
Wu, Kaichun
Xia, Limin
author_facet Feng, Weibo
Chen, Jie
Huang, Wenjie
Wang, Guodong
Chen, Xilang
Duan, Lili
Yin, Yue
Chen, Xiaoping
Zhang, Bixiang
Sun, Mengyu
Luo, Xiangyuan
Nie, Yongzhan
Fan, Daiming
Wu, Kaichun
Xia, Limin
author_sort Feng, Weibo
collection PubMed
description Background: Metastasis is a major cause of HCC-related deaths with no effective pharmacotherapies. Chronic inflammation promotes HCC dissemination, however, its underlying mechanisms are not fully understood. Here, we investigated the role of Krüppel-like factor 7 (KLF7) in inflammation-provoked HCC metastasis and proposed therapeutic strategies for KLF7-positive patients. Methods: The expression of KLF7 in human HCC specimens were examined by immunohistochemistry and quantitative real-time PCR. The luciferase reporter assays and chromatin immunoprecipitation assays were conducted to explore the transcriptional regulation related to KLF7. Orthotopic xenograft models and DEN/CCl(4)-induced HCC models were established to evaluate HCC progression and metastasis. Results: KLF7 overexpression promotes HCC metastasis through transactivating toll-like receptor 4 (TLR4) and protein tyrosine kinase 2 (PTK2) expression. High mobility group box 1 (HMGB1) upregulates KLF7 expression through the TLR4/advanced glycosylation end-product specific receptor (RAGE)-PI3K-AKT-NF-κB pathway, forming an HMGB1-KLF7-TLR4 positive feedback loop. The HMGB1-KLF7-TLR4/PTK2 axis is gradually activated during the progression of inflammation-HCC transition. Genetic depletion of KLF7 impedes HMGB1-mediated HCC progression and metastasis. The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. In human HCCs, KLF7 expression is positively correlated with cytoplasmic HMGB1, p-p65, TLR4, and PTK2 levels, and patients positively co-expressing HMGB1/KLF7, p-p65/KLF7, KLF7/TLR4 or KLF7/PTK2 exhibit the worst prognosis. Conclusions: HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients.
format Online
Article
Text
id pubmed-10405848
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-104058482023-08-08 HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2 Feng, Weibo Chen, Jie Huang, Wenjie Wang, Guodong Chen, Xilang Duan, Lili Yin, Yue Chen, Xiaoping Zhang, Bixiang Sun, Mengyu Luo, Xiangyuan Nie, Yongzhan Fan, Daiming Wu, Kaichun Xia, Limin Theranostics Research Paper Background: Metastasis is a major cause of HCC-related deaths with no effective pharmacotherapies. Chronic inflammation promotes HCC dissemination, however, its underlying mechanisms are not fully understood. Here, we investigated the role of Krüppel-like factor 7 (KLF7) in inflammation-provoked HCC metastasis and proposed therapeutic strategies for KLF7-positive patients. Methods: The expression of KLF7 in human HCC specimens were examined by immunohistochemistry and quantitative real-time PCR. The luciferase reporter assays and chromatin immunoprecipitation assays were conducted to explore the transcriptional regulation related to KLF7. Orthotopic xenograft models and DEN/CCl(4)-induced HCC models were established to evaluate HCC progression and metastasis. Results: KLF7 overexpression promotes HCC metastasis through transactivating toll-like receptor 4 (TLR4) and protein tyrosine kinase 2 (PTK2) expression. High mobility group box 1 (HMGB1) upregulates KLF7 expression through the TLR4/advanced glycosylation end-product specific receptor (RAGE)-PI3K-AKT-NF-κB pathway, forming an HMGB1-KLF7-TLR4 positive feedback loop. The HMGB1-KLF7-TLR4/PTK2 axis is gradually activated during the progression of inflammation-HCC transition. Genetic depletion of KLF7 impedes HMGB1-mediated HCC progression and metastasis. The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. In human HCCs, KLF7 expression is positively correlated with cytoplasmic HMGB1, p-p65, TLR4, and PTK2 levels, and patients positively co-expressing HMGB1/KLF7, p-p65/KLF7, KLF7/TLR4 or KLF7/PTK2 exhibit the worst prognosis. Conclusions: HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients. Ivyspring International Publisher 2023-07-14 /pmc/articles/PMC10405848/ /pubmed/37554278 http://dx.doi.org/10.7150/thno.84388 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
Feng, Weibo
Chen, Jie
Huang, Wenjie
Wang, Guodong
Chen, Xilang
Duan, Lili
Yin, Yue
Chen, Xiaoping
Zhang, Bixiang
Sun, Mengyu
Luo, Xiangyuan
Nie, Yongzhan
Fan, Daiming
Wu, Kaichun
Xia, Limin
HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2
title HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2
title_full HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2
title_fullStr HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2
title_full_unstemmed HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2
title_short HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2
title_sort hmgb1-mediated elevation of klf7 facilitates hepatocellular carcinoma progression and metastasis through upregulating tlr4 and ptk2
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405848/
https://www.ncbi.nlm.nih.gov/pubmed/37554278
http://dx.doi.org/10.7150/thno.84388
work_keys_str_mv AT fengweibo hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT chenjie hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT huangwenjie hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT wangguodong hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT chenxilang hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT duanlili hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT yinyue hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT chenxiaoping hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT zhangbixiang hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT sunmengyu hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT luoxiangyuan hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT nieyongzhan hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT fandaiming hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT wukaichun hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2
AT xialimin hmgb1mediatedelevationofklf7facilitateshepatocellularcarcinomaprogressionandmetastasisthroughupregulatingtlr4andptk2