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      Single nucleotide polymorphisms within the Wnt pathway predict the risk of bone metastasis in patients with non-small cell lung cancer

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          Abstract

          The Wingless-type (Wnt) signaling pathway plays an important role in the development and progression of cancer. This study aimed to evaluate the relationship between single nucleotide polymorphisms (SNPs) in the Wnt pathway and the risk of bone metastasis in patients with non-small cell lung cancer (NSCLC). We collected 500 blood samples from patients with NSCLC and genotyped eight SNPs from four core genes (WNT2, AXIN1, CTNNB1 and APC) present within the WNT pathway. Moreover, we assessed the potential relationship of these genes with bone metastasis development. Our results showed that the AC/AA genotype of CTNNB1: rs1880481 was associated with a decreased risk of bone metastasis. Polymorphisms with an HR of < 1 had a cumulative protective impact on the risk of bone metastasis. Furthermore, patients with the AC/AA genotype of CTNNB1: rs1880481 was associated with Karnofsky performance status score, squamous cell carcinoma antigen and Ki-67 proliferation index. Lastly, patients with the AC/AA genotype of CTNNB1: rs1880481 had significantly longer median progression free survival time than those with the CC genotype. In conclusion, SNPs within the Wnt signaling pathway are associated with a decreased risk of bone metastasis, and may be valuable biomarkers for bone metastasis in patients with NSCLC.

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          Functions of RANKL/RANK/OPG in bone modeling and remodeling.

          Brendan F Boyce, Lianping Xing (2008)
          The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.
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            Wnt/beta-catenin signaling regulates cancer stem cells in lung cancer A549 cells.

            Ying Teng, Xiuwen Wang, Yawei Wang … (2010)
            Wnt/beta-catenin signaling plays an important role not only in cancer, but also in cancer stem cells. In this study, we found that beta-catenin and OCT-4 was highly expressed in cisplatin (DDP) selected A549 cells. Stimulating A549 cells with lithium chloride (LiCl) resulted in accumulation of beta-catenin and up-regulation of a typical Wnt target gene cyclin D1. This stimulation also significantly enhanced proliferation, clone formation, migration and drug resistance abilities in A549 cells. Moreover, the up-regulation of OCT-4, a stem cell marker, was observed through real-time PCR and Western blotting. In a reverse approach, we inhibited Wnt signaling by knocking down the expression of beta-catenin using RNA interference technology. This inhibition resulted in down-regulation of the Wnt target gene cyclin D1 as well as the proliferation, clone formation, migration and drug resistance abilities. Meanwhile, the expression of OCT-4 was reduced after the inhibition of Wnt/beta-catenin signaling. Taken together, our study provides strong evidence that canonical Wnt signaling plays an important role in lung cancer stem cell properties, and it also regulates OCT-4, a lung cancer stem cell marker.
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              Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies.

              Serena Ricciardi, Alberto Fulvi, Antonio Passaro … (2014)
              Bone and brain metastases are a very common secondary localization of disease in patients with lung cancer. The prognosis of these patients is still poor with a median survival of less than 1 year. Current therapeutic approaches include palliative radiotherapy and systemic therapy with chemotherapy and targeted agents. For bone metastasis, zoledronic acid is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events (SREs). Recently, denosumab, a fully human monoclonal antibody directed against the receptor activator of nuclear factor κB (RANK) ligand inhibiting the maturation of pre-osteoclasts into osteoclasts, showed increased time to SREs and overall survival compared with zoledronic acid. The treatment of brain metastasis is still controversial. Available standard therapeutic options, such as whole brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. More recently, novel target agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and afatinib have shown activity in patients with brain metastasis. Inter alia, in patients harboring EGFR mutations, the administration of EGFR TKIs is followed by a response rate of 70-80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. This review is focused on the evidence for therapeutic strategies in bone and brain metastases due to lung cancer.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging (Albany NY)
                Journal ID (iso-abbrev): Aging (Albany NY)
                Journal ID (publisher-id): Aging
                Title: Aging (Albany NY)
                Publisher: Impact Journals
                ISSN (Electronic): 1945-4589
                Publication date Collection: 31 May 2020
                Publication date (Electronic): 26 May 2020
                Volume: 12
                Issue: 10
                Pages: 9311-9327
                Affiliations
                [1 ]Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China
                [2 ]Department of Respiratory Medicine and Critical Care Medicine, Fujian Provincial Hospital, Fuzhou 350001, China
                [3 ]Fujian Provincial Researching Laboratory of Respiratory Diseases, Fuzhou 350001, China
                [4 ]Department of Medical Oncology, Longyan First Hospital Affiliated to Fujian Medical University, Longyan 364000, China
                Author notes
                [*]

                Equal contribution

                Correspondence to: Yusheng Chen; email: cysktz2019@163.com
                Article
                Publisher ID: 103207 Publisher ID: 103207
                DOI: 10.18632/aging.103207
                PMC ID: 7288946
                PubMed ID: 32453708
                SO-VID: 54bbb4ed-789c-403b-a781-73e310d21015
                Copyright © Copyright © 2020 Xu et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 30 December 2019
                Date accepted : 17 April 2020
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Cell biology
                Keywords: wnt signaling pathway,polymorphisms,bone metastasis,risk,biomarker
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: wnt signaling pathway, polymorphisms, bone metastasis, risk, biomarker

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