We investigated post-translational modification and subcellular localisation of endogenous platelet-derived growth factor-C (PDGF-C) in human thyroid papillary carcinomas (PTC), non-neoplastic thyroid tissues, and a selection of cultured cell lines. PDGF-C expressed nuclear localisation in 95% of all tested cell types in culture and in 10% of the thyrocytes from both PTC and non-neoplastic tissue. The cell lines expressed two forms of full-length PDGF-C, approximately 39 and approximately 55 kDa, in cell membrane and cytosol, while the approximately 55 kDa form dominated in the nucleus where it was partly chromatin-associated. The approximately 55 kDa form was post-translationally modified by SUMO-1. The putative PDGF-C SUMOylation site is the surface exposed (314)lysine part of a positively charged loop ((312)RPKTGVRGLHK(322)) with characteristics of a nuclear localisation signal. The tissue thyrocytes expressed a non-SUMOylated approximately 43 kDa and the 55 kDa PDGF-C. The SUMO-1 modified approximately 55 kDa PDGF-C expression was low in PTC where the approximately 43 kDa PDGF-C dominated. This is in contrast to non-neoplastic tissue and cultured cells where the SUMOylated approximately 55 kDa PDGF-C was strongly expressed. Our data provide novel evidence for nuclear localisation of PDGF-C, post-translational modification by SUMOylation and the expression of a novel form of PDGF-C in human papillary thyroid carcinomas.

Bone resorption, caused by osteoclasts (OCs), is important to bone homeostasis. The abnormalities of bone resorption may induce a series of diseases, including osteoarthritis, osteoporosis and aseptic peri-implant loosening. The latest research developed,a novel tyrosine and phosphoinositide kinase dual inhibitor, named PP121, inhibited Src in anaplastic thyroid carcinoma cell. However, the therapeutic function of PP121 on abnormal bone resorption is still uncertain. In the present study, we showed that PP121 could potently suppress osteoclast differentiation, osteoclast-specific gene expression and bone resorption via suppressing Src/MAPK (ERK and p38)/Akt-mediated NFATc1 induction in vitro. \It was found that PP121 could suppress the formation of osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, inhibit bone resorption and downregulate the mRNA level of osteoclast-specific markers, including calcitonin receptor (CTR), tartrate resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase 3 (MMP3), Cellular oncogene fos (C-Fos) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Consistent with in vitro observation, we found that PP121 greatly ameliorated LPS-induced bone resorption. Our results provide promising evidence of the therapeutic potential of PP121 for osteolytic diseases related to excessive osteoclast-mediated bone resorption.