p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone

Abstract

Giant cell tumor of bone (GCTB) is an intermediate (locally aggressive) bone tumor with a recurrence rate of >30% following surgery. GCTB recurrence is ultimately due to the proliferation of neoplastic stromal (NS) cells. However, the precise mechanism underlying the regulation of NS cell proliferation remains unknown. p62 protein is a multifunctional adaptor protein that exerts a positive role in bone tumors and metabolic bone diseases. In the present study, the mRNA and protein expression levels of p62 were detected by reverse transcription-quantitative PCR and western blotting, respectively, in 8 paired fresh GCTB tumor tissues and adjacent normal cancellous bone tissues. The association between p62 expression level and patient prognosis was subsequently analyzed in 54 paraffin-embedded tumor specimens by immunohistochemistry assay. NS cells were isolated from GCTB primary cell culture, and the role of p62 was evaluated using in vitro cell proliferation, migration and invasion assays. The results revealed that p62 mRNA and protein were overexpressed in tumor tissues. High p62 expression levels were significantly associated with the recurrence of GCTB (P=0.001). The patients in the high p62 expression group had shorter 5-year recurrence-free survival rates compared with the patients in the low p62 expression group (P<0.001). Cox regression analysis identified p62 expression as an independent prognostic indicator of the recurrence-free survival of patients with GCTB (P<0.001). The in vitro experiments revealed that p62 downregulation inhibited NS cell proliferation, invasion and migration, and promoted apoptosis. In conclusion, it was found that p62 overexpression is associated with the recurrence of GCTB via the promotion of NS cell proliferation. Therefore, p62 could be a novel prognostic indicator, and a potential therapeutic target for GCTB.

Updated concepts in treatment of giant cell tumor of bone

“…P62 is known to be overexpressed in bone tumors like osteosarcoma and myeloma and associated with tumor invasion and metastasis. Liu et al have linked p62 expression to increased recurrence rates in GCTB; this could be useful as prognostic biomarker and therapeutic target [54 ▪ ].…”

Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy

“…They proposed Beclin1 as a target for blocking autophagy and sensitizing cancer cells to chemotherapeutic drugs [399,400]. Recently, overexpression of p62, a selective autophagy receptor, has been shown to be associated with giant cell tumor of bone (GCTB) recurrence [401].…”

Human Chorionic Gonadotropin Regulates the Smad Signaling Pathway by Antagonizing TGF-β in Giant Cell Tumor of Bone

“…Giant cell tumor of bone (GCTB) is a locally aggressive tumor [ 1 ] comprised of multiple cell types, including osteoclast-like multinucleated giant cells, monocytic round-shaped macrophage-like cells, and spindle-shaped fibroblast-like stromal cells [ 2 ]. Pathologically, primary stromal cells are the main tumor components of GCTB, and the proliferation and metastasis of stromal cells induce the recurrence of GCTB [ 3 , 4 ]. Thus, elucidating the molecular mechanisms that promote the growth of stromal cells in GCTB is expected to provide strategies to alleviate GCTB.…”