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  • br The role of P in tumors

    2019-05-22


    The role of P62 in tumors
    The role of P62 in osteoclastogenesis
    P62 as an oncotarget for treatment
    Concluding remarks P62 is a cellular “Swiss army knife,” with its diverse cellular functions arising from its unique functional motifs and protein–protein interaction properties. P62 may play different roles in different type RG7112 or different states of cells. For example, in tumor cells, P62 accumulation results in perturbation of gene expression, increased genome damage and tumorigenesis [6]. However, in tumor stromal cells, P62 up-regulation is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism [93]. At the same time, its multifunctional nature may contribute to its complex role in osteolytic metastasis. For example, the up-regulation of P62 can promote osteoclastogenesis and differentiation by activating RANKL–RANK-NF-κB signaling, thereby accelerating bone resorption. This implies that P62 may promote osteolytic metastasis. However, as a receptor protein of autophagy, P62 accumulated because of autophagy failure, which hampered osteolytic metastasis. This implies that P62 may be, contradictorily, a reducer of osteolytic metastasis. In another example, as previously noted, the P62-NRF2-autophagy signal feedback loop includes two contradictory types, also playing an important role in osteoclastogenesis, and appears to be similar to the P62-mTOR-autophagy feedback in fat metabolism [94]. As a whole, these apparently contradictory roles showed that P62 is a multi-domain protein that may play different roles in different types of cells and in different microenvironments. Nevertheless, the ability of P62 to modulate tumors and osteoclasts suggests that it may be a feasible oncotarget for bone metastasis, especially for osteolytic metastasis. P62 may be an attractive target for therapeutic intervention if we are able to selectively modulate the interactions of P62 with specific signaling molecules, perhaps by using different interaction modules inherent in its structure. Molecule targeted therapy is an important developing direction for tumor treatments, and the key to its success is the identification of crucial molecular targets. The mechanism of osteolytic metastasis involves different types of cells and intricate molecular signaling. P62 is at the interface of both tumor cells and osteoclasts, at the juncture of different signaling pathways that are correlated with tumorigenesis, metastasis and bone turnover. Therefore, selective regulation of P62 expression may be a feasible strategy for bone metastasis, especially for osteolytic metastasis. To date, several animal studies using the P62 vaccine showed broad-spectrum anti-tumor, anti-metastatic and anti-osteoporotic activity. A number of human clinical trials of DNA vaccines have been performed or are ongoing for tumors and showed encouraging results [95]. Further studies should be designed to detect P62 expression in osteolytic metastasis tissues. Meanwhile, evaluating the curative effects of down-regulating P62 expression in osteolytic metastasis animal models may provide an experimental basis for new targeted treatments.
    Competing interests
    Authors contributions
    Acknowledgments This research was supported in part by Grants (no. 81302343/H1624) from the National Natural Science Foundation of China, a Grant (no. 2014FB0 592014FB067) from the Joint Special Funds for the Department of Science and Technology of Yunnan Province – Kunming Medical University.