HMGB1 promotes cellular proliferation and invasion, suppresses cellular apoptosis in osteosarcoma

Abstract

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Unfortunately, treatment failures are common due to the metastasis and chemoresistance, but the underlying molecular mechanism remains unclear. Accumulating evidence indicated that the deregulation of DNA-binding protein high-mobility group box 1 (HMGB1) was associated with the development of cancer. This study aimed to explore the expression of HMGB1 in osteosarcoma tissues and its correlation to the clinical pathology of osteosarcoma and to discuss the role of HMGB1 in the development of osteosarcoma. The results from RT-PCR and Western blot showed that the expression rate of HMGB1 messenger RNA (mRNA) and the expression of HMGB1 in the osteosarcoma tissues were significantly higher than those in normal bone tissue (p < 0.05), the expression rate of HMGB1 mRNA and the expression of HMGB1 in the carcinoma tissues with positive lung metastasis were significantly higher than those without lung metastasis (p < 0.05), and with increasing Enneking stage, the expression rate of HMGB1 mRNA and the expression of HMGB1 also increased (p < 0.05). In order to explore the role of HMGB1 in osteosarcoma, the expression of HMGB1 in the human osteosarcoma MG-63 cell line was downregulated by the technique of RNA interference. Western blot results showed that the protein expression of HMGB1 was significantly decreased in the MG-63 cells from HMGB1-siRNA transfection group (p < 0.05), which suggested that HMGB1 was successfully downregulated in the MG-63 cells. Then the changes in proliferation, apoptosis, and invasion of MG-63 cells were examined by MTT test, PI staining, annexin V staining, and transwell chamber assay. Results showed that the abilities of proliferation and invasion were suppressed in HMGB1 knockdown MG-63 cells, and the abilities of apoptosis were enhanced in HMGB1 knockdown MG-63 cells. The expression of cyclin D1, MMP-9 was downregulated in HMGB1 knockdown MG-63 cells, and the expression of caspase-3 was upregulated in HMGB1 knockdown MG-63 cells. Taken together, the overexpression of HMGB1 in osteosarcoma might be related to the tumorigenesis, invasion, and metastasis of osteosarcoma, which might be a potential target for the treatment of osteosarcoma.

Interference with HMGB1 increases the sensitivity to chemotherapy drugs by inhibiting HMGB1-mediated cell autophagy and inducing cell apoptosis

“…Additionally, HMGB proteins are subdivided into HMGB1, HMGB2, and HMGB3, all of which contain two HMG-box domains and a highly acidic Cterminal tail [10,11]. The current study found the expression levels of HMGB1 gene were significantly higher than that of the corresponding normal tissues in a variety of tumor tissues, including colorectal cancer, breast cancer, pancreatic cancer, melanoma, et al, which suggested that HMGB1 was involved in the occurrence and development of tumors [12][13][14][15][16]. Dong found that knockdown of the HMGB1 expression inhibited tumor growth and metastasis in human liver cancer through AKT-mediated regulation of Ki-67 and MMP-2 expression [17].…”

The role of high‐mobility group protein box 1 in lung cancer

“…Previous studies showed that the increased expression of HMGB1 in many malignant tumors has been associated with progressive tumor proliferation, invasion, metastasis, and poor prognosis, for example, hepatocellular carcinoma, osteosarcoma, bladder cancer, gastric cancer, colon cancer, breast cancer, and mesothelioma. [70][71][72][73][74][75][76][77][78][79][80] Besides, the overexpression of HMGB1 was closely related to the level of tumor invasion and the stage of lymph node metastasis in colon and colorectal cancer. 81 Of note, the overexpression of HMGB1, TLR4, and MyD88 are correlated with tumor-node-metastasis stage and lymph node metastasis in gastric cancer, which proves poor prognosis.…”

Necrosis of osteosarcoma cells induces the production and release of high‑mobility group box 1 protein

“…Previous studies have reported that high-mobility group box 1 protein (HMGB1) was a critical factor in the development of chemoresistance (14)(15)(16), and notably, that it promoted drug resistance in osteosarcoma, thus suggesting a novel target for improving osteosarcoma therapy (15,(17)(18)(19). Recently, Meng et al (20) observed that the tumorigenesis, invasion and metastasis of osteosarcoma was associated with overexpression of HMGB1, which may thus be a potential target for treatment (20). However, to the best of our knowledge, it has not been clarified whether HMGB1 is involved in cell necrosis during the development and progression of osteosarcomas.…”