The mir-423-5p/MMP-2 Axis Regulates the Nerve Growth Factor-Induced Promotion of Chondrosarcoma Metastasis

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Abstract

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A chondrosarcoma is a common tumor of the bone that has a high propensity to metastasize to distant organs. The effects of NGF in a chondrosarcoma are not confirmed although NGF is capable of promoting the progression and metastasis of several different types of tumors. Here, we found that NGF promotes the chondrosarcoma migration and metastasis in vitro and in vivo. The levels of NGF and MMP-2 in human chondrosarcoma tumor tissues correlated strongly with the tumor stage. We identified that NGF induces the MMP-2 synthesis and chondrosarcoma cell motility by inhibiting miR-423-5p expression through the FAK and c-Src pathways. We suggest that NGF is a worthwhile therapeutic target in the treatment of a metastatic chondrosarcoma.

Abstract

A chondrosarcoma is a common tumor of the soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is capable of promoting the progression and metastasis of several different types of tumors although the effects of NGF in a chondrosarcoma are not confirmed. Here, we found that the levels of NGF and matrix metalloproteinase-2 (MMP-2) correlated with the tumor stage in patients with a chondrosarcoma. NGF facilitated the MMP-2-dependent cellular migration in human chondrosarcoma JJ012 cells while the overexpression of NGF enhanced the lung metastasis in a mouse model of a chondrosarcoma. NGF promoted the MMP-2 synthesis and cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades. NGF appears to be a worthwhile therapeutic target in the treatment of a metastatic chondrosarcoma.

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Targeting metastasis.

Patricia S Steeg (2016)

Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients. Therapeutic goals are the prevention of an initial metastasis in high-risk patients, shrinkage of established lesions and prevention of additional metastases in patients with limited disease. Instead of being autonomous, tumour cells engage in bidirectional interactions with metastatic microenvironments to alter antitumour immunity, the extracellular milieu, genomic stability, survival signalling, chemotherapeutic resistance and proliferative cycles. Can targeting of these interactions significantly improve patient outcomes? In this Review preclinical research, combination therapies and clinical trial designs are re-examined.

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The role and mechanisms of action of microRNAs in cancer drug resistance

Wengong Si, Jiaying Shen, Huilin Zheng … (2019)

MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.

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MicroRNA in lung cancer: role, mechanisms, pathways and therapeutic relevance

Mohammad Iqbal, Shweta Arora, Gopinath Prakasam … (2018)

Lung cancer is the cardinal cause of cancer-related deaths with restricted recourse of therapy throughout the world. Clinical success of therapies is not very promising due to - late diagnosis, limited therapeutic tools, relapse and the development of drug resistance. Recently, small ∼20-24 nucleotides molecules called microRNAs (miRNAs) have come into the limelight as they play outstanding role in the process of tumorigenesis by regulating cell cycle, metastasis, angiogenesis, metabolism and apoptosis. miRNAs essentially regulate gene expression via post-transcriptional regulation of mRNA. Nevertheless, few studies have conceded the role of miRNAs in activation of gene expression. A large body of data generated by numerous studies is suggestive of their tumor-suppressing, oncogenic, diagnostic and prognostic biomarker roles in lung cancer. They have also been implicated in regulating cancer cell metabolism and resistance or sensitivity towards chemotherapy and radiotherapy. Further, miRNAs have also been convoluted in regulation of immune checkpoints - Programmed death 1 (PD-1) and its ligand (PD-L1). These molecules play a significant role in tumor immune escape leading to the generation of a microenvironment favouring tumor growth and progression. Therefore, it is imperative to explore the expression of miRNA and understand its relevance in lung cancer and development of anti-cancer strategies (anti - miRs, miR mimics and micro RNA sponges). In view of the above, the role of miRNA in lung cancer has been dissected and the associated mechanisms and pathways are discussed in this review.

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Author and article information

Contributors

Katsuhiro Hayashi: Role: Academic Editor

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 03 July 2021

Publication date Collection: July 2021

Volume: 13

Issue: 13

Electronic Location Identifier: 3347

Affiliations

[1 ]Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; tzhuen@ 123456tmu.edu.tw

[2 ]Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan

[3 ]Division of Hematology/Oncology, Department of Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan

[4 ]School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

[5 ]Translational Medicine Research Center, China Medical University Hospital, Taichung 40402, Taiwan; T34946@ 123456mail.cmuh.org.tw

[6 ]International Master Program of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan; u107206102@ 123456cmu.edu.tw

[7 ]Department of Orthopedic Surgery, China Medical University Hospital, Taichung 40402, Taiwan; D14333@ 123456mail.cmuh.org.tw

[8 ]School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan; Jufangliu@ 123456tmu.edu.tw

[9 ]Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan; u105305004@ 123456cmu.edu.tw

[10 ]Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan; u9957651@ 123456cmu.edu.tw

[11 ]Department of Sports Medicine, College of Health Care, China Medical University, Taichung 40402, Taiwan

[12 ]Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin 65152, Taiwan

[13 ]Department of Biotechnology, College of Health Science, Asia University, Taichung 41354, Taiwan

[14 ]Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan

Author notes

[* ]Correspondence: d1762@ 123456mail.bh.cmu.edu.tw (Y.-C.F.); chtang@ 123456mail.cmu.edu.tw (C.-H.T.)

[†]

Co-first author: These authors contributed equally to this work.

Author information

Chih-Yuan Ko https://orcid.org/0000-0001-7752-2833

Chih-Hsin Tang https://orcid.org/0000-0002-7113-8352

Article

Publisher ID: cancers-13-03347

DOI: 10.3390/cancers13133347

PMC ID: 8268073

SO-VID: d257d870-278e-4b1c-a589-f0dda2e4e816

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

The mir-423-5p/MMP-2 Axis Regulates the Nerve Growth Factor-Induced Promotion of Chondrosarcoma Metastasis

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Microbiology Independent Research Journal (MIR Journal)

Most cited references 57

Targeting metastasis.

The role and mechanisms of action of microRNAs in cancer drug resistance

MicroRNA in lung cancer: role, mechanisms, pathways and therapeutic relevance

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