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    • It is established that hypoxia can induce autophagy

    2019-04-29

    It is established that hypoxia can induce autophagy [32,34–37]. We evidenced the autophagic activation in the cultured human osteosarcoma MG-63 carboxypeptidase after incubation in 1% O2 for 24h. The concomitantly elevated LC3 protein levels with HIF-1α high expression on OS tissue sections also indicates hypoxia might have activated autophagy in human OS tissues. A recent publication also supports our study [38]. This report demonstrated that irradiation induced ROS accumulation which led to DNA damage in mesenchymal stem cells. However, this toxic effect was reduced by autophagic induction, supporting the notion that autophagy has an important role in conferring cells the tolerance to irradiation. Consistently, the hypoxia-induced autophagy has also been evidence in other radioresistant cancers [23,28,39]. How autophagy is activated in OS needs be further studied. Proteins and pathways like HIF-1α, BNIP3, MAP1LC3B, ATG5, ATF4, AMPK, etc., have been reported to have mechanistic roles in hypoxia-induced autophagic activation [32,40–44]. The recent advancement of next generation sequencing technologies might reveal more specific clues by comprehensive analyses of the entire molecular profiles from the clinical OS tissues with proper controls [45–50].
    Conflict of interest
    Acknowledgements The authors thank all of the lab members for helpful discussion. This work was supported by the National Natural Science Foundation of China (No. 81201607) and the Project of the Natural Science Foundation of Hebei Province (No. H2015206314) Helin Feng.
    Introduction Osteosarcoma is one of the most common primary bone malignancies, with an incidence of 4–5 cases per million people, mainly in adolescents and young adults [1]. Osteosarcoma localizes to the proximal tibia or the distal femur and has a highly malignant tendency to destroy the surrounding normal tissues and to metastasize [2,3]. Although there have been advancements in treatment therapies, including chemotherapy, radiotherapy and tumor excision strategies, it has been reported that approximately 50% of patients with osteosarcoma develop metastases, which results in a low cure rate and a low 5-year survival rate [4]. Therefore, it is important to develop new strategies for the early diagnosis of osteosarcoma to improve treatment strategies and the prognostic outcomes in these patients. Although previous studies have shown that some molecular targets are related to tumorigenesis, the molecular mechanism underlying osteosarcoma has not been fully elucidated. Consequently, it is difficult to develop strategies for the effective diagnosis and prognosis of osteosarcoma [5,6]. Therefore, it is important to understand the molecular mechanisms of osteosarcoma in order to identify novel diagnostic and prognostic markers that will improve the clinical prognosis of osteosarcoma patients. MicroRNAs (miRNAs) are a class of small noncoding and endogenous regulatory RNA molecules that are approximately 19–25 nucleotides in length [7,8]. Studies have shown that miRNAs regulate target gene expression by either inducing messenger RNA (mRNA) degradation through perfect base-pairing or inhibiting mRNA translation via imperfect base-pairing in the seed sequence using the 3′-untranslated region (UTR) of target mRNAs [9,10]. Aberrant expression of miRNAs has been observed in human cancers and has been shown to be involved in a variety of critical cellular processes, including cell differentiation, proliferation and metabolism [11]. In addition, the expression profiles of miRNAs in plasma and serum samples have been used to accurately classify human cancers, which suggest that miRNAs could potentially be used as a diagnostic and prognostic marker of cancer [12]. MicroRNA-223 (miR-223) is a hematopoietic specific microRNA with crucial functions in myeloid lineage development [13]. Previous studies have found that miR-223 is repressed in several human cancers, such as hepatocellular carcinoma, acute lymphoblastic leukemia, gastric MALT lymphoma and recurrent ovarian cancer [14–17]. Recently, Xu et al. [18] demonstrated that miR-223 was a tumor suppresser in osteosarcoma and showed that miR-223/Ect2/p21 signaling played a role in osteosarcoma cell cycle progression and proliferation. However, the role of miR-223 expression in the diagnosis and prognosis of osteosarcoma has not been reported.
    Materials and methods
    Results
    Discussion Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common type of primary bone malignancy [20]. Over the past few decades, the introduction of combinatorial chemotherapy has improved the 5-year overall survival rate of patients with osteosarcoma to approximately 50–60% [21]. However, osteosarcoma-related morbidity remains high due to the difficulty of early diagnosis and the lack of efficient therapeutic approaches for osteosarcoma. Therefore, it is necessary to identify highly sensitive and specific diagnostic and prognostic biomarkers to diagnose osteosarcoma at an early stage and initiate aggressive therapy.