CacyBP/SIP promotes tumor progression by regulating apoptosis and arresting the cell cycle in osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumor in pediatric and adolescent patients. The calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) performs an essential function in cell proliferation and apoptosis. The present study investigated the effect of CacyBP/SIP in OS cell proliferation and apoptosis. CacyBP/SIP mRNA expression levels were evaluated in four OS cell lines by quantitative PCR. CacyBP/SIP expression was downregulated in Saos-2 cells using a lentivirus transfection system and the transfection efficiency was analyzed. The effects of CacyBP/SIP downregulation on Saos-2 cell proliferation and colony-formation ability were evaluated by MTT and colony-formation assays. The effect of CacyBP/SIP knockdown on Saos-2 cell cycle and apoptosis was analyzed by flow cytometry cell sorting. The Cancer Genome Atlas (TCGA) data was analyzed for validation. Human OS cell lines Saos-2, MG-63, HOS and U20S expressed CacyBP/SIP mRNA. CacyBP/SIP knockdown significantly inhibited cell proliferation and colony-formation ability. G1/S phase arrest was induced by CacyBP/SIP downregulation, which also resulted in the downregulation of CDK and cyclins and the upregulation of p21. In addition, CacyBP/SIP downregulation induced Saos-2 cell apoptosis mediated by Bax and Bcl-2. High expression of CacyBP/SIP was significantly associated with poor prognosis in TCGA sarcoma database. Thus, CacyBP/SIP performs important functions in the proliferation and apoptosis of human OS cells.

Short-term Preoperative Denosumab With Surgery in Unresectable or Recurrent Giant Cell Tumor of Bone.

OBJECTIVE: The purpose of this retrospective study was to evaluate the clinical and oncological results of combination treatment of short-term preoperative denosumab (the receptor activator of nuclear factor kappa-B ligand inhibitor) with surgery in unresectable or recurrent cases of giant cell tumor of the bone (GCTB). METHODS: Between 2016 and 2018, 11 eligible patients (1 man, 10 women, mean age 38.1 years) with grade 3 GCTB were treated with a combination of short-term (six doses) preoperative denosumab and surgery in a single institution. The clinical, radiological, and pathological alteration after the denosumab treatment were compared. The oncological results of the combination therapy were also recorded. Meanwhile, adverse effects or complications of denosumab, if any, were reported. RESULTS: The median follow-up time after surgical procedure was 30 months (range 13-45 months). After 3-4 denosumab injections, pain relief was observed in all patients. In two spine patients, the neurological status improved after four doses of treatment. Intraoperatively, the margin of the tumor became clear and the intensity of the tumor increased while the blood supply around and within the lesion decreased. Within the lesion, the typically soft and loose tissue were replaced by the tough and dense fibro-osseous tissue. The mean diameter of the lesion before and after treatment was 61.55 ± 22.49 mm and 51.81 ± 21.12 mm, respectively, and the T-score was 1.02 (P = 0.32). Variable calcification was observed at the periphery and within the lesion. A total of three patients experienced local recurrence in this study. In the resection group, only one extremity patient had soft tissue recurrence that was treated with en-bloc excision. In the curettage group, two of three sacral tumor patients had local occurrence. Both refused re-operation and restarted the monthly denosumab injection thereafter, and the lesions remained stable at the final follow up. Finally, no adverse effects or complications related to denosumab treatment were found. CONCLUSION: For the unresectable or recurrent GCTB cases, short-term (six doses) preoperative use of denosumab improved clinical symptoms, decreased the tumor size, and increased the tumor density. The changes in tumors, in turn, simplified the tumor removal manipulation and, subsequently, decreased the local recurrence for the resection surgery. For the curettage, the denosumab-induced changes had mixed impacts, and shorter term (fewer than six doses) usage may be more appropriate. Our six-dose regime was deemed safe, while the safety of long-term use remains unknown.