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ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14

High aggressiveness is the main reason for the poor prognosis of hepatocellular carcinoma (HCC) patients. However, its molecular mechanisms still remain largely unexplored. ACADL, a mitochondrial enzyme that facilitates the primary regulated step in mitochondrial fatty acid oxidation, plays a role i...

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Autores principales: Guo, Danfeng, Zhang, Xiaodan, Cui, Honglei, Yu, Dongsheng, Zhang, Huapeng, Shi, Xiaoyi, Pang, Chun, Li, Jie, Guo, Wenzhi, Zhang, Shuijun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841782/
https://www.ncbi.nlm.nih.gov/pubmed/35174091
http://dx.doi.org/10.3389/fonc.2022.821484
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author Guo, Danfeng
Zhang, Xiaodan
Cui, Honglei
Yu, Dongsheng
Zhang, Huapeng
Shi, Xiaoyi
Pang, Chun
Li, Jie
Guo, Wenzhi
Zhang, Shuijun
author_facet Guo, Danfeng
Zhang, Xiaodan
Cui, Honglei
Yu, Dongsheng
Zhang, Huapeng
Shi, Xiaoyi
Pang, Chun
Li, Jie
Guo, Wenzhi
Zhang, Shuijun
author_sort Guo, Danfeng
collection PubMed
description High aggressiveness is the main reason for the poor prognosis of hepatocellular carcinoma (HCC) patients. However, its molecular mechanisms still remain largely unexplored. ACADL, a mitochondrial enzyme that facilitates the primary regulated step in mitochondrial fatty acid oxidation, plays a role in HCC growth inhibition. However, the function of ACADL in tumor metastasis is not well elucidated. We found that the reduced expression of ACADL is closely associated with the loss of tumor encapsulation, extrahepatic metastasis, and poor prognosis in HCC patients. Upregulation of ACADL significantly inhibited HCC migration and invasion ability. Whereas knockdown of ACADL markedly enhanced cell invasive capability. Expression of matrix metalloproteinase-14 (MMP14) was negatively associated with the content of ACADL in HCC specimens. MMP14-positive patients with a low expression of ACADL showed worse outcome. Treatment with MMP14 agonist reversed the inhibitory effect of ACADL on HCC metastasis. In addition, ACADL negatively regulated MMP14 expression by inhibiting the STAT3 signaling pathway, as the sustained activation of STAT3 effectively restored the level of MMP14 in ACADL-overexpressed cells. Collectively, these findings disclose that ACADL represses HCC metastasis via STAT3-MMP14 pathway. This study may propose a promising strategy for the precise treatment of metastatic HCC patients.
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spelling pubmed-88417822022-02-15 ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14 Guo, Danfeng Zhang, Xiaodan Cui, Honglei Yu, Dongsheng Zhang, Huapeng Shi, Xiaoyi Pang, Chun Li, Jie Guo, Wenzhi Zhang, Shuijun Front Oncol Oncology High aggressiveness is the main reason for the poor prognosis of hepatocellular carcinoma (HCC) patients. However, its molecular mechanisms still remain largely unexplored. ACADL, a mitochondrial enzyme that facilitates the primary regulated step in mitochondrial fatty acid oxidation, plays a role in HCC growth inhibition. However, the function of ACADL in tumor metastasis is not well elucidated. We found that the reduced expression of ACADL is closely associated with the loss of tumor encapsulation, extrahepatic metastasis, and poor prognosis in HCC patients. Upregulation of ACADL significantly inhibited HCC migration and invasion ability. Whereas knockdown of ACADL markedly enhanced cell invasive capability. Expression of matrix metalloproteinase-14 (MMP14) was negatively associated with the content of ACADL in HCC specimens. MMP14-positive patients with a low expression of ACADL showed worse outcome. Treatment with MMP14 agonist reversed the inhibitory effect of ACADL on HCC metastasis. In addition, ACADL negatively regulated MMP14 expression by inhibiting the STAT3 signaling pathway, as the sustained activation of STAT3 effectively restored the level of MMP14 in ACADL-overexpressed cells. Collectively, these findings disclose that ACADL represses HCC metastasis via STAT3-MMP14 pathway. This study may propose a promising strategy for the precise treatment of metastatic HCC patients. Frontiers Media S.A. 2022-01-31 /pmc/articles/PMC8841782/ /pubmed/35174091 http://dx.doi.org/10.3389/fonc.2022.821484 Text en Copyright © 2022 Guo, Zhang, Cui, Yu, Zhang, Shi, Pang, Li, Guo and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Guo, Danfeng
Zhang, Xiaodan
Cui, Honglei
Yu, Dongsheng
Zhang, Huapeng
Shi, Xiaoyi
Pang, Chun
Li, Jie
Guo, Wenzhi
Zhang, Shuijun
ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14
title ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14
title_full ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14
title_fullStr ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14
title_full_unstemmed ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14
title_short ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14
title_sort acadl functions as a tumor suppressor in hepatocellular carcinoma metastasis by inhibiting matrix metalloproteinase 14
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841782/
https://www.ncbi.nlm.nih.gov/pubmed/35174091
http://dx.doi.org/10.3389/fonc.2022.821484
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