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FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism

Patients with cervical cancer (CCa) with lymph node metastasis (LNM) have an extremely poor prognosis. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa. Upregulation of fatty acid-binding protein 5 (FABP5) expression in CCa tumours was demons...

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Autores principales: Zhang, Chunyu, Liao, Yuandong, Liu, Pan, Du, Qiqiao, Liang, Yanchun, Ooi, Shiyin, Qin, Shuhang, He, Shanyang, Yao, Shuzhong, Wang, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295046/
https://www.ncbi.nlm.nih.gov/pubmed/32550890
http://dx.doi.org/10.7150/thno.44868
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author Zhang, Chunyu
Liao, Yuandong
Liu, Pan
Du, Qiqiao
Liang, Yanchun
Ooi, Shiyin
Qin, Shuhang
He, Shanyang
Yao, Shuzhong
Wang, Wei
author_facet Zhang, Chunyu
Liao, Yuandong
Liu, Pan
Du, Qiqiao
Liang, Yanchun
Ooi, Shiyin
Qin, Shuhang
He, Shanyang
Yao, Shuzhong
Wang, Wei
author_sort Zhang, Chunyu
collection PubMed
description Patients with cervical cancer (CCa) with lymph node metastasis (LNM) have an extremely poor prognosis. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa. Upregulation of fatty acid-binding protein 5 (FABP5) expression in CCa tumours was demonstrated to positively correlate with LNM. However, the precise role and mechanisms of FABP5 in the LNM of CCa remain unknown. Methods: The diagnostic value of FABP5 as a predictor of LNM in CCa was evaluated in CCa tumour samples. The functional role of FABP5 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. A mouse model of LNM was used to determine the effect of FABP5 on LNM and the therapeutic value of FABP5 targeting. Results: We demonstrated that FABP5 was markedly upregulated in CCa with LNM and correlated with poor prognosis. FABP5 protein was an independent predictor of LNM in a multivariate logistic analysis. Furthermore, FABP5 promoted epithelial-mesenchymal transition, lymphangiogenesis, and LNM by reprogramming fatty acid (FA) metabolism. Mechanistically, FABP5 promoted lipolysis and FA synthesis, which led to an increase in intracellular fatty acids (FAs) that activated NF-κB signalling, thus inducing LNM. Importantly, administration of orlistat, which attenuates FA metabolism reprogramming, inhibited FABP5-induced LNM in CCa. The pro-metastatic effect of FABP5 was reduced by miR-144-3p. Moreover, miR-144-3p was significantly downregulated and FABP5 was upregulated in CCa in a hypoxic microenvironment. Conclusion: Our findings highlight a FA metabolism-dependent mechanism of FABP5-induced LNM. Moreover, the expression and biological function of FABP5 can be regulated by miR-144-3p in hypoxia. Our study identifies FABP5 as a potential diagnostic biomarker and therapeutic target for LNM in CCa.
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spelling pubmed-72950462020-06-17 FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism Zhang, Chunyu Liao, Yuandong Liu, Pan Du, Qiqiao Liang, Yanchun Ooi, Shiyin Qin, Shuhang He, Shanyang Yao, Shuzhong Wang, Wei Theranostics Research Paper Patients with cervical cancer (CCa) with lymph node metastasis (LNM) have an extremely poor prognosis. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa. Upregulation of fatty acid-binding protein 5 (FABP5) expression in CCa tumours was demonstrated to positively correlate with LNM. However, the precise role and mechanisms of FABP5 in the LNM of CCa remain unknown. Methods: The diagnostic value of FABP5 as a predictor of LNM in CCa was evaluated in CCa tumour samples. The functional role of FABP5 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. A mouse model of LNM was used to determine the effect of FABP5 on LNM and the therapeutic value of FABP5 targeting. Results: We demonstrated that FABP5 was markedly upregulated in CCa with LNM and correlated with poor prognosis. FABP5 protein was an independent predictor of LNM in a multivariate logistic analysis. Furthermore, FABP5 promoted epithelial-mesenchymal transition, lymphangiogenesis, and LNM by reprogramming fatty acid (FA) metabolism. Mechanistically, FABP5 promoted lipolysis and FA synthesis, which led to an increase in intracellular fatty acids (FAs) that activated NF-κB signalling, thus inducing LNM. Importantly, administration of orlistat, which attenuates FA metabolism reprogramming, inhibited FABP5-induced LNM in CCa. The pro-metastatic effect of FABP5 was reduced by miR-144-3p. Moreover, miR-144-3p was significantly downregulated and FABP5 was upregulated in CCa in a hypoxic microenvironment. Conclusion: Our findings highlight a FA metabolism-dependent mechanism of FABP5-induced LNM. Moreover, the expression and biological function of FABP5 can be regulated by miR-144-3p in hypoxia. Our study identifies FABP5 as a potential diagnostic biomarker and therapeutic target for LNM in CCa. Ivyspring International Publisher 2020-05-17 /pmc/articles/PMC7295046/ /pubmed/32550890 http://dx.doi.org/10.7150/thno.44868 Text en © The author(s) 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
Zhang, Chunyu
Liao, Yuandong
Liu, Pan
Du, Qiqiao
Liang, Yanchun
Ooi, Shiyin
Qin, Shuhang
He, Shanyang
Yao, Shuzhong
Wang, Wei
FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
title FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
title_full FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
title_fullStr FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
title_full_unstemmed FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
title_short FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
title_sort fabp5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295046/
https://www.ncbi.nlm.nih.gov/pubmed/32550890
http://dx.doi.org/10.7150/thno.44868
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