Abstract
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.
Highlights
20% of osteosarcoma patients exhibit lung metastasis when diagnosed, while an additional 40% develop lung metastasis in advanced stages, which correlates with poor 5-year survival rates [1]
It has been demonstrated that high positive coactivator 4 (PC4) www.impactjournals.com/oncotarget expression in osteosarcoma correlates with poor prognosis, and suppression of PC4 blocked the pulmonary metastasis by reducing malignancy phenotype through transcriptional level depression of MMP9
The data gathered in this part implied that PC4 was increased in osteosarcoma
Summary
20% of osteosarcoma patients exhibit lung metastasis when diagnosed, while an additional 40% develop lung metastasis in advanced stages, which correlates with poor 5-year survival rates [1]. PC4 was found to highly expressed in human prostate stromal cells at the embryonic stage and declined to significantly lower levels by adulthood, while elevated in prostate cancer associated stroma[7]. As osteosarcoma is believed to originate from mesenchymal cells, we sought to evaluate the potential function of PC4 in osteosarcoma tumorigenesis and pulmonary metastasis. In this context, it has been demonstrated that high PC4 www.impactjournals.com/oncotarget expression in osteosarcoma correlates with poor prognosis, and suppression of PC4 blocked the pulmonary metastasis by reducing malignancy phenotype through transcriptional level depression of MMP9. Our findings imply that PC4 may be an effective potential therapeutic gene to inhibit osteosarcoma tumorigenesis and prevent lung metastasis
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