PDGF-BB regulates the transformation of fibroblasts into cancer-associated fibroblasts via the lncRNA LURAP1L-AS1/LURAP1L/IKK/IκB/NF-κB signaling pathway

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Abstract

The most abundant cells in the tumor microenvironment are cancer-associated fibroblasts (CAFs). They play an important role in oral squamous cell carcinoma (OSCC) angiogenesis, invasion and metastasis. Platelet-derived growth factor (PDGF)-BB has an obvious regulating effect on the formation of CAFs through binding to PDGF receptor (PDGFR)-β, but the role of long non-coding (lnc)RNA in PDGF-BB-induced transformation of fibroblasts into CAFs remains poorly understood. Using an lncRNA ChIP, 370 lncRNA transcripts were identified to be significantly and differentially expressed between fibroblasts and PDGF-BB-induced fibroblasts, including 240 upregulated lncRNAs and 130 downregulated lncRNAs, indicating that lncRNAs are involved in the regulation of the transformation of CAFs. Previous studies have shown that the nuclear factor (NF)-κB signaling pathway plays an important role in the activation of CAFs. Dual-luciferase reporter assay and co-immunoprecipitation were conducted to confirm that the leucine-rich adaptor protein 1-like (LURAP1L), which is the target of lncRNA LURAP1L antisense RNA 1 (LURAP1L-AS1) had a positive regulatory effect on I-κB kinase (IKK)/NF-κB signaling. Therefore, LURAP1L-AS1 was selected and PDGF-BB was demonstrated to upregulate the expression of LURAP1L-AS1 and LURAP1L, which was reversed by a PDGFR-β inhibitor. Subsequently, knocking down LURAP1L-AS1 suppressed the expression of PDGF-BB-induced fibroblast activation marker protein α-smooth muscle actin, fibroblast activation protein-α, PDGFR-β and phosphorylated (p)-PDGFR-β. IKKα, p-IĸB and p-NF-κB were downregulated by the knockdown of LURAP1L-AS1 and upregulated by overexpression of LURAP1L-AS1. The present study indicates that LURAP1L-AS1/LURAP1L/IKK/IĸB/NF-κB plays an important regulatory role in PDGF-BB-induced fibroblast activation and may become a potential target for the treatment of OSCC.

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

Kenneth Livak, Thomas D. Schmittgen (2001)

The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).

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The biology and function of fibroblasts in cancer.

Raghu Kalluri (2016)

Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells. Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components. CAFs have a role in creating extracellular matrix (ECM) structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy. The pleiotropic actions of CAFs on tumour cells are probably reflective of them being a heterogeneous and plastic population with context-dependent influence on cancer.

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Author and article information

Journal

Journal ID (nlm-ta): Oncol Lett

Journal ID (iso-abbrev): Oncol Lett

Journal ID (publisher-id): OL

Title: Oncology Letters

Publisher: D.A. Spandidos

ISSN (Print): 1792-1074

ISSN (Electronic): 1792-1082

Publication date (Print): July 2021

Publication date (Electronic): 19 May 2021

Publication date PMC-release: 19 May 2021

Volume: 22

Issue: 1

Electronic Location Identifier: 537

Affiliations

[1 ]Department of Periodontology, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, Yunnan 530102, P.R. China

[2 ]Department of Head and Neck Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China

[3 ]Department of Otolaryngology, Kunming Children's Hospital, Kunming, Yunnan 650034, P.R. China

[4 ]Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, Yunnan 530102, P.R. China

[5 ]Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China

Author notes

Correspondence to: Dr Yongwen He, Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, 1088 Haiyuan Central Road, Kunming, Yunnan 530102, P.R. China, E-mail: heyongwen2@ 123456sina.com

Dr Li Bian, Department of Pathology, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, Yunnan 650032, P.R. China, E-mail: bianli1976@ 123456sina.com

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Article

Publisher ID: OL-0-0-12798

DOI: 10.3892/ol.2021.12798

PMC ID: 8157341

PubMed ID: 34079593

SO-VID: f8b9849d-1c1b-452a-829b-54fc55d78191

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 16 June 2020

Date accepted : 18 March 2021

Funding

Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;

Award ID: 81660448

Award ID: 81360401

Funded by: Special Health Technical Personnel Training program of Yunnan, China

Award ID: L-201612

Funded by: Natural Science Foundation of Yunnan, China

Award ID: 2017FE468-006

The present study was supported by the National Natural Science Foundation of China (grant no. 81660448 and 81360401), the Special Health Technical Personnel Training program of Yunnan, China (grant no. L-201612) and the Natural Science Foundation of Yunnan, China (grant number 2017FE468-006).

PDGF-BB regulates the transformation of fibroblasts into cancer-associated fibroblasts via the lncRNA LURAP1L-AS1/LURAP1L/IKK/IκB/NF-κB signaling pathway

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Karger: Oncology

Most cited references 49

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

The biology and function of fibroblasts in cancer.

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