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Velvet Antler Compounds Targeting Major Cell Signaling Open Chem., 2019; 17: 235–245 Review Article Zhengyao Zhang, Pengfei Li, Tie Li, Changwei Zhao, Guoxiang Wang* Velvet Antler compounds targeting major cell signaling pathways in osteosarcoma - a new insight into mediating the process of invasion and metastasis in OS https://doi.org/10.1515/chem-2019-0028 received May 17, 2018; accepted September 6, 2018. 1 Introduction Abstract: Velvet antler is the only renewable bone tissue Osteosarcoma, derived from primitive bone-forming of mammalian animals, which consists of a variety mesenchymal cells, is the most common primary bone of growth factors, amino acids and polypeptides. But malignancy that occurs most frequently in adolescents the mechanism of high-speed proliferation without and elders over the age of 60 [1]. Osteosarcoma most carcinogenesis is still mystifying. The previous study frequently affects the growing ends of long bones and is of this work found that the velvet antler peptides (VAP) often located adjacent to joints. Approximately one-half could not only inhibit the proliferation and migration of all osteosarcomas affects the knee region, with the of osteosarcoma cell lines MG-63 and U2OS, but also distal femur being the most commonly affected site [2]. induced U2OS apoptosis and inhibited MG-63 epithelial- Osteosarcoma is characterized by destruction of bone mesenchymal transition (EMT) through TGF-β and Notch and soft tissue and is highly likely to be accompanied by pathways. These results lead us to conclude that VAP has metastasis of the cancer cells to the distal organ, where the potential ability to mediate osteosarcoma cells by metastasis to the lung accounts for approximately 80%, regulating related signaling pathways and growth factors. with a poor prognosis. If clinical metastasis occurs, the Therefore, finding a new appropriate inhibitor for OS is patient’s five-year survival rate is between 20%-30% by the a valuable research direction, which will give patients a combination of conventional surgery and chemotherapy better chance to receive proper therapy. From an applied [3]. Deer velvet antler is one of the most important perspective, this review summarized the effects of velvet conventional Chinese medicines, the application of antler, genes, growth factors and research progress of which was started two thousand years ago. It has been relative pathways and genes of osteosarcoma, which are extensively used in traditional Chinese medicine (TCM) to poised to help link regenerative molecular biology and treat a variety of diseases including degenerative disease regenerative medicine in osteosarcoma pathogenesis. (osteoarthritis), auto-immune or auto-inflammatory processes (rheumatoid arthritis and ankylosing Keywords: osteosarcoma; velvet antler; growth factors; spondylitis), infection (septic arthritis), idiopathic pathways; EMT. (juvenile idiopathic arthritis) and kidney diseases and so on. In a decade, researchers have extracted velvet antler peptides (VAP) by using ion exchange chromatography, gel filtration chromatography and high-performance *Corresponding author: Guoxiang Wang, Cancer Center, The First liquid chromatography. Hence, the velvet antler contains Hospital of Jilin University, Changchun Jilin 130021, China, E-mail: a lot of growth factors such as insulin-like growth factor [email protected]; (IGF), nerve growth factor (NGF), epidermal growth Changwei Zhao, Department of Orthopedics, Changchun University factor (EGF) and transforming growth factor (TGF), of Chinese Medicine, Changchun Jilin 130021, China which have different influences on osteosarcoma cells Zhengyao Zhang, Pengfei Li: School of Life Science and Medicine, [4,5]. In addition, the progression of osteosarcoma is Dalian University of Technology, DaGong Road, Panjin Liaoning 124221, China regulated by signaling pathways such as TGF-β, which Tie Li: Acupuncture and Tuina Institute, Changchun University of can mediate the pro-apoptosis effects by doxorubicin [6] Chinese Medicine, Changchun Jilin 130021, China , and the inhibition of the Notch pathway can suppresses Open Access. © 2019 Zhengyao Zhang et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution alone 4.0 License. 236 Zhengyao Zhang et al. Table 1: Summary of the validated growth factors in preclinical experiments of osteosarcoma. Growth factors Target Functions in cancer Sirtuin 6[17] MMP9 Migration and invasion ERK1/2 Fractalkine[18] CX3CR1 Osteosarcoma metastasis EZH2[19] TUG1 tumorigenesis NKD2[20] unclear Tumor growth and metastasis HIF1α[21] COX2 Carcinogenesis VEGF Metastasis Endocannabinoid/Endovanilloid [22] CB1/2 Anti-proliferative, pro-apoptotic Anti-invasive CCL5/CCR5[23] VEGF Tumor angiogenesis BMP-9[24] Smad Cell apoptosis Bcl-2 Proliferation and metastasis MALAT1[25] PI3K/AKT Proliferation and metastasis osteosarcoma growth [7]. Wnt-β-catenin and PI3K/Akt can related in OS and discusses some clinical options in order influence osteosarcoma cell proliferation and growth [8], to maintain or even improve progression-free survival. and NF-κB can be used as a target to induce osteosarcoma cells apoptosis [9], thus the molecule-targeted treatment of tumors should be widely considered. Pathway research provides the basis for study of osteosarcoma 2 Diagnosis and possible target diagnosis and drug targets. At the same time, during the therapies for osteosarcoma progress of osteosarcoma formation, many genes have mutated expression and modified abnormally, including In the recent years, the diagnosis and therapies of oncogene (Sema4d, Sema6d, ZNF217 and ZNF592) [10], osteosarcoma have been improved a lot by the efforts tumor suppressor gene (Period2, Bax and P53) [11,12] and of researchers. The conventional methods of diagnosis tumor migration gene (RANKL, CXCR4, RB1, MDM2) [13]. include performing biopsy of pathology tissue, magnetic Identified and screened mutated genes and abnormally resonance imaging (MRI), computed tomography (CT), expressed genes are very important to treat and diagnose positron emission tomography (PET) and so on. The osteosarcoma. Chen et.al have found the extracts of velvet new method which used to diagnose osteosarcoma antler had a dose-response relationship for osteosarcoma aims at detecting biomarkers including microRNAs, cell-line UMR-106, when the concentration was higher than long non-coding RNAs, circulating tumor cells, and 0.972mg/L and lower than 97.2mg/L, samples inhibited the circulating tumor DNA. There are a lot of advantages in proliferation of the cells, when the concentration reached the new method, called liquid biopsy, when compared 97.2ml/L the role will change to promote, and the effects to conventional methods, such as, low sample volume, are increased with an increase in protein concentration greater accuracy, less expensive, and easy detection [1,15]. [14]. However, its molecular mechanism is still unclear, Several pieces of evidence strongly support the which needs further study. Meanwhile, we have found potential capability of new therapies such as cellular that VAPs can inhibit the proliferation and migration of therapy and gene therapy to eradicate osteosarcoma. osteosarcoma cell lines MG-63 and U2OS. The VAP can Thus, clinical human trials using peptides, cytokines and also induce U2OS apoptosis and inhibit MG-63 epithelial- dendritic cells have been performed [16]. Investigators mesenchymal transition (EMT), while TGF-β and Notch have found a variety of growth factors and microRNAs pathways regulate these interactions. Thus, how far have which have effective impact on osteosarcoma. These we moved forward and what therapeutic strategy should findings can be innovative therapies for osteosarcoma to we prefer for anti-pathway therapy? This review provides improve survival and prognosis. an overview of the most updated pathways and genes Velvet Antler compounds targeting major cell signaling pathways in osteosarcoma... 237 Table 2: Summary of the validated microRNA in preclinical experiments of osteosarcoma. microRNA Target Functions in cancer miR-137[26] FXYD6 Cell growth miR-154[27] Wnt5a Tumor suppressor miR-646[28] FGF2 Osteosarcoma cells metastasis miR-23a[29] PTEN Cell migration and invasion miR-153[30] TGF-β2 Cell proliferation and invasion miR-221[31] PI3K Osteosarcoma cells survival Cisplatin resistance miR-29b[32] CDK6 Osteosarcoma cells proliferation Cells metastasis miR-150[33] ROCK1 Osteosarcoma cells proliferation Invasion and migration miR-543[34] PRMT9 Osteosarcoma cells proliferation and glycolysis HIF-1α miR-16[35] IGF1R Cell proliferation 3 Gene mutated in Cancer Bone osteosarcoma cells could increase event-free survival and overall survival significantly. Moreover, a decreased Disease level of ErbB2 was associated with poor prognosis of osteosarcoma patients. Thus, ErbB2 might serve as a There are numerous gene mutations and changes in potential therapeutic biomarker target for predicting expression in the process of osteosarcoma compared with the chemotherapy progress as an illustrative example normal people. It plays a pivotal role to identify and screen [41]. COX2 also known as PTGS encodes the inducible mutated genes for diagnosing and treating osteosarcoma. isozyme. It is required for tumoursphere formation, but It is widely believed that cell carcinogenesis and tumor tumourspheres increase invasiveness and tumourigenicity metastasis are caused by changes in genetic information. in osteosarcoma. Therefore, it could be a potential target to It has been found that some mutations and aberrant treat
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