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CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datase...

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Autores principales: Pan, Zongfu, Xu, Tong, Bao, Lisha, Hu, Xiaoping, Jin, Tiefeng, Chen, Jinming, Chen, Jianqiang, Qian, Yangyang, Lu, Xixuan, li, Lu, Zheng, Guowan, Zhang, Yiwen, Zou, Xiaozhou, Song, Feifeng, Zheng, Chuanming, Jiang, Liehao, Wang, Jiafeng, Tan, Zhuo, Huang, Ping, Ge, Minghua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531463/
https://www.ncbi.nlm.nih.gov/pubmed/36192735
http://dx.doi.org/10.1186/s12943-022-01658-x
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author Pan, Zongfu
Xu, Tong
Bao, Lisha
Hu, Xiaoping
Jin, Tiefeng
Chen, Jinming
Chen, Jianqiang
Qian, Yangyang
Lu, Xixuan
li, Lu
Zheng, Guowan
Zhang, Yiwen
Zou, Xiaozhou
Song, Feifeng
Zheng, Chuanming
Jiang, Liehao
Wang, Jiafeng
Tan, Zhuo
Huang, Ping
Ge, Minghua
author_facet Pan, Zongfu
Xu, Tong
Bao, Lisha
Hu, Xiaoping
Jin, Tiefeng
Chen, Jinming
Chen, Jianqiang
Qian, Yangyang
Lu, Xixuan
li, Lu
Zheng, Guowan
Zhang, Yiwen
Zou, Xiaozhou
Song, Feifeng
Zheng, Chuanming
Jiang, Liehao
Wang, Jiafeng
Tan, Zhuo
Huang, Ping
Ge, Minghua
author_sort Pan, Zongfu
collection PubMed
description Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-022-01658-x.
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spelling pubmed-95314632022-10-05 CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment Pan, Zongfu Xu, Tong Bao, Lisha Hu, Xiaoping Jin, Tiefeng Chen, Jinming Chen, Jianqiang Qian, Yangyang Lu, Xixuan li, Lu Zheng, Guowan Zhang, Yiwen Zou, Xiaozhou Song, Feifeng Zheng, Chuanming Jiang, Liehao Wang, Jiafeng Tan, Zhuo Huang, Ping Ge, Minghua Mol Cancer Research Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-022-01658-x. BioMed Central 2022-10-03 /pmc/articles/PMC9531463/ /pubmed/36192735 http://dx.doi.org/10.1186/s12943-022-01658-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Pan, Zongfu
Xu, Tong
Bao, Lisha
Hu, Xiaoping
Jin, Tiefeng
Chen, Jinming
Chen, Jianqiang
Qian, Yangyang
Lu, Xixuan
li, Lu
Zheng, Guowan
Zhang, Yiwen
Zou, Xiaozhou
Song, Feifeng
Zheng, Chuanming
Jiang, Liehao
Wang, Jiafeng
Tan, Zhuo
Huang, Ping
Ge, Minghua
CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment
title CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment
title_full CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment
title_fullStr CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment
title_full_unstemmed CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment
title_short CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment
title_sort creb3l1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531463/
https://www.ncbi.nlm.nih.gov/pubmed/36192735
http://dx.doi.org/10.1186/s12943-022-01658-x
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