Wei-wei Shen

CD147 deficiency blocks IL-8 secretion and inhibits lung cancer-induced osteoclastogenesis.

Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and poor prognosis; however, the molecular basis of this process is still unknown. This study investigated the role of extracellular matrix metalloproteinase inducer (also known as cluster of differentiation (CD)147) in osteoclastogenesis resulting from bone metastasis, based on the enrichment of this glycoprotein on the surface of many malignant bone tumors. RNA interference was used to silence CD147 expression in A549 human lung cancer cells. Compared with conditioned medium (CM) from control cells (A549-CM), CM from CD147-deficient cells (A549-si-CM) suppressed receptor activator of nuclear factor κB ligand-stimulated osteoclastogenesis in RAW 264.7 cells and bone marrow-derived macrophages. The mRNA levels of osteoclast-specific genes such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K were also reduced in the presence of A549-si-CM. CD147 knockdown in A549 cells decreased interleukin (IL)-8mRNA and protein expression. IL-8 is present in large amounts in A549-CM and mimicked its inductive effect on osteoclastogenesis; this was reversed by depletion of IL-8 from the medium. Taken together, these results indicate that CD147 promotes lung cancer-induced osteoclastogenesis by modulating IL-8 secretion, and suggest that CD147 is a potential therapeutic target for cancer-associated bone resorption in lung cancer patients.

Single-nucleotide polymorphisms of the PRKCG gene and osteosarcoma susceptibility

The objective of this study was to explore the relationship between single-nucleotide polymorphisms (SNPs) of the protein kinase C gamma (PRKCG) gene and osteosarcoma susceptibility in Chinese Han population. A total of 610 cases of osteosarcoma patients and 610 healthy individuals were enrolled in this study. TaqMan method was used to compare genotypes and the allelic distribution frequency of three SNPs (rs454006, rs2242245, and rs8103851) in the PRKGG gene between osteosarcoma patients and healthy individuals. Osteosarcoma patients were grouped according to different clinical parameters (age, gender, pathological types, tumor location, Enneking staging, tumor metastasis and treatment) to compare genotype and allele frequency among different groups as well as to explore the relationship between gene polymorphisms and different clinical parameters. The rs454006 polymorphisms of the PRKCG gene include the CC, CT, and TT genotypes. The differences in genotype frequency and allele frequency between osteosarcoma patients and healthy individuals were significant (both P < 0.001). There was no significant different between osteosarcoma patients and healthy individuals in rs8103851 and rs2242245 polymorphisms of the PRKCG gene (both P > 0.05). The differences of the rs8103851 genotype frequency and allele frequency in patients with metastatic osteosarcoma and patients without metastasis were significant (both P < 0.001). The distribution frequencies of the CG and GG genotypes as well as the G allele in patients with metastatic osteosarcoma were higher than in patients without metastasis. The genotype frequency and allele frequency of rs454006 and rs2242245 did not correlate with clinical parameters. The rs454006 polymorphism of the PRKCG gene correlated to osteosarcoma susceptibility and might increase the risk of osteosarcoma. The rs8103851 correlated to metastatic osteosarcoma and could be risk factors for metastatic osteosarcoma.

Prostate cancer cells induce osteoblastic differentiation via semaphorin 3A.

Prostate cancer metastasis to bone is the second most commonly diagnosed malignant disease among men worldwide. Such metastatic disease is characterized by the presence of osteoblastic bone lesions, and is associated with high rates of mortality. However, the various mechanisms involved in prostate cancer‐induced osteoblastic differentiation have not been fully explored. Semaphorin 3A (Sema 3A) is a newly identified regulator of bone metabolism which stimulates differentiation of pre‐osteoblastic cells under physiological conditions. We investigated in this study whether prostate cancer cells can mediate osteoblastic activity through Sema 3A.

Quetiapine inhibits osteoclastogenesis and prevents human breast cancer-induced bone loss through suppression of the RANKL-mediated MAPK and NF-κB signaling pathways

Bone loss is one of the major complications of advanced cancers such as breast cancer, prostate cancer, and lung cancer. Extensive research has revealed that the receptor activator of NF-κB ligand (RANKL), which is considered to be a key factor in osteoclast differentiation, plays an important role in cancer-associated bone resorption. Therefore, agents that can suppress this bone loss have therapeutic potential. In this study, we detected whether quetiapine (QUE), a commonly used atypical antipsychotic drug, can inhibit RANKL-induced osteoclast differentiation in vitro and prevent human breast cancer-induced bone loss in vivo. RAW 264.7 cells and bone marrow-derived macrophages (BMMs) were used to detect inhibitory effect of QUE on osteoclastogenesis in vitro. Mouse model of breast cancer metastasis to bone was used to test suppressive effect of QUE on breast cancer-induced bone loss in vivo. Our results show that QUE can inhibit RANKL-induced osteoclast differentiation from RAW 264.7 cells and BMMs without signs of cytotoxicity. Moreover, QUE reduced the occurrence of MDA-MB-231 cell-induced osteolytic bone loss by suppressing the differentiation of osteoclasts. Finally, molecular analysis revealed that it is by inhibiting RANKL-mediated MAPK and NF-κB signaling pathways that QUE suppressed the osteoclast differentiation. We demonstrate, for the first time, the novel suppressive effects of QUE on RANKL-induced osteoclast differentiation in vitro and human breast cancer-induced bone loss in vivo, suggesting that QUE may be a potential therapeutic drug for osteolysis treatment.

Down regulation of human positive coactivator 4 suppress tumorigenesis and lung metastasis of osteosarcoma

Osteosarcoma is a kind of primary malignant bone tumor with the highest incidence and an extraordinarily poor prognosis and early pulmonary metastasis formation as a frequent occurrence. Transcriptional positive coactivator 4 (PC4) has multiple functions in DNA replication, transcription, repair and chromatin organization, even in tumorigenesis. However, the precise function of PC4 in osteosarcoma is still unclear and controversial. In this paper we found PC4 was upregulated in patient-derived osteosarcoma tissues compared to normal. Moreover, higher expression of PC4 was correlated with poorer overall survival and advanced clinicopathological tumor staging. Down regulation of PC4 in the highly metastatic osteosarcoma cells reduced the malignant behaviors in vitro and in vivo. Analyzing the downstream genes affected obviously by shPC4 with RNA sequencing, we found knocking down PC4 will inhibit the propensity for lung metastasis through transcriptional suppression of MMPs pathways. Taken together, PC4 may be an attractive therapeutic strategy for osteosarcoma, especially in preventing lung metastasis formation.Osteosarcoma is a kind of primary malignant bone tumor with the highest incidence and an extraordinarily poor prognosis and early pulmonary metastasis formation as a frequent occurrence. Transcriptional positive coactivator 4 (PC4) has multiple functions in DNA replication, transcription, repair and chromatin organization, even in tumorigenesis. However, the precise function of PC4 in osteosarcoma is still unclear and controversial. In this paper we found PC4 was upregulated in patient-derived osteosarcoma tissues compared to normal. Moreover, higher expression of PC4 was correlated with poorer overall survival and advanced clinicopathological tumor staging. Down regulation of PC4 in the highly metastatic osteosarcoma cells reduced the malignant behaviors in vitro and in vivo. Analyzing the downstream genes affected obviously by shPC4 with RNA sequencing, we found knocking down PC4 will inhibit the propensity for lung metastasis through transcriptional suppression of MMPs pathways. Taken together, PC4 may be an attractive therapeutic strategy for osteosarcoma, especially in preventing lung metastasis formation.