br Conclusions br Limitation br Acknowledgments This researc

Conclusions
Limitation
Acknowledgments This research was supported in part by the China Postdoctoral Science Foundation (Nos. 2013M542478 and 2015T81139), a Grant (no. 2014FB059) from the Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University, a Grant (no. D-201242) from the specialty fund of High-level Talents Medical Personnel Training of Yunnan Province. A Grant (no. 2015HC026) from the Yunnan Provincial Innovative Team of Bone and Soft Tissue Tumor. A Grant (no. 2014HB034) from the Young and Middle-aged Academic and Technical Leaders of Yunnan Province, Grant (no. 2014NS013/2014NS014/2014NS016) from the Health Medical Units with Research Institutions Construction Project of Yunnan Province, and Doctor Scientific Research Startup funds of the Third Affiliated Hospital of Kunming Medical University (No. BSJJ201406).
Introduction Up to 90% of patients with multiple myeloma, and 60–75% patients with prostate cancer and breast cancer develop bone metastasis at the later stages of their diseases [1]. Metastatic lesions in bone are significantly associated with bone pain, hypercalcemia or hypocalcemia, pathological fracture and spinal cord compression, which mostly correlated to low 5-years survival-rate less than 30% [2]. Relative to osteoblastic metastasis, osteolytic metastasis is more difficult to treat, making the need to study its pathogenesis. Recent advances in the understanding of osteolytic metastasis revealed that it is associated with characteristic modulations of the bone microenvironment and crosstalk between the tumor GSK2126458 and bone cells (primarily the osteoclasts). Tumor cells condition the “metastatic niche” through the secretion of soluble factors that stimulate bone resorption by the osteoclasts. Osteoclastic bone resorption results in the release and activation of growth factors in the bone microenvironment that further stimulate tumor growth, leading to a “vicious cycle” [3]. It is involved with numerous signaling factors, but the crucial molecules are still uncertain [1]. Since its initial discovery as an atypical protein kinase C (PKC)-interacting protein, P62 (also known as sequestosome-1, SQSTM-1 or A170) has emerged as a crucial molecule in the regulation of cell growth, survival and proliferation [4]. The human P62 protein has 440 amino acid residues and contains different types of protein–protein interaction domains. The multi-functional domains of the P62 adapter protein are consistent with its role as a versatile multitasker in signal transduction in tumors [5], (Fig. 1). P62 accumulation promotes tumorigenesis [6]. It is found to be either not expressed or found at low levels of expression in normal tissues, but is over-expressed among various types of tumors and, for the most part, is correlated with tumor migration, invasion or metastasis [7–24]. Thus, the P62 gene is generally acknowledged to be an oncogene. In addition, many studies on Paget\'s disease of bone (PDB), which is a skeletal disorder characterized by osteolytic lesions and overactive osteoclasts, have identified P62 as an important modulator of the osteoclastogenesis pathway [25–27]. The dysregulated expression of the P62 protein promotes osteoclastogenesis, bone resorption and osteolytic lesions. Therefore, P62 has long been thought of as a promising molecular target in PDB and other bone metabolic diseases [28]. Many in vitro and in vivo studies employing knockdown have shown that P62 can inhibit tumor formation, proliferation and/or progression [29–31]. Recent research on intramuscularly or intravenously administered P62 DNA vaccines showed that they induced anti-P62 antibodies and exhibited strong anti-tumor and anti-metastatic activities in transplantable mouse tumors [32] and canine spontaneous mammary neoplasm models [33]. The latest research reported the unexpected finding that intramuscular delivery of P62 DNA vaccines exerts a powerful anti-osteoporotic activity in a mouse model of inflammatory bone loss [34]. These studies promoted P62 as an oncotarget for bone metastasis, especially for osteolytic metastasis.