MAT1 facilitates the lung metastasis of osteosarcoma through upregulation of AKT1 expression
Introduction
Osteosarcoma is the most common primary malignant bone tumor affecting children and adolescents. It is mainly derived from the metaphysis of long bone and is inclined to local invasion and distant metastases, with lung metastasis as the most common type [[1], [2], [3]]. Despite that patients' prognosis has been improved due to the application of combination therapy of chemoradiotherapy and surgical resection [4,5], the five-year survival rates of patients with lung metastasis are still dim, with ~30% [6]. Therefore, further exploration of the mechanisms underlying the lung metastasis in osteosarcoma is of importance.
It's well documented that cyclin-dependent kinases (CDKs) play important roles in modulating cell proliferation via controlling cell cycle [7]. The phosphorylation of CDKs is executed by CDK-activating kinase (CAK) [8,9], which is a trimeric complex consisting of CDK7 [10], Cyclin H [11], and the accessory protein, MAT1 (MNAT1) [12,13]. MAT1 gathers CAK and determines the substrate specificity of CAK, and then regulates cell cycle G1 exit [14]. Through MAT1, CAK interacts with and phosphorylates retinoblastoma tumor suppressor protein (Rb), a proliferation repressor and a differentiation promoter [15,16]. However, MAT1 deletion impedes the phosphorylation of Rb and induces G1 arrest in osteosarcoma cells [14], suggesting that MAT1 may play a role in the progression of osteosarcoma. Noticeably, inhibition of the expression and phosphorylation of Rb plays an important role in the metastasis of various kinds of cancers. For example, Arima et al. [17] demonstrated that downregulation of Rb with siRNA interference in breast cancer MCF-7 cells destroyed cell-cell adhesion and promoted the epithelial-to-mesenchymal transition (EMT), which was closely implicated in the metastasis of primary tumors. Berman et al. [18] found that mice with Rb and p53 double mutant were viable and displayed multiple characteristics of human osteosarcomas, including high metastasis. These findings suggest that MAT1 might be involved in the metastasis of osteosarcoma.
As a result, this study aimed to explore the effects of MAT1 on the metastasis of osteosarcoma, especially for lung metastasis, as well as reveal its underlying mechanisms.
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Patients
All tissue samples used in this study were obtained from osteosarcoma patients who received an osteosarectomy with/without a pneumonectomy. In detail, 8 osteosarcoma tissues were obtained from patients with no pulmonary metastasis; 8 osteosarcoma tissues were acquired from patients with pulmonary metastasis and another 8 lung tissues were gained from patients with pulmonary metastasis. Experiments involving human samples were approved by the ethical committee of the 2nd Xiangya Hospital,
High expression of MAT1 closely associates with osteosarcoma patients' advanced clinical stage and lung metastasis
To explore the effects of MAT1 in the lung metastasis of osteosarcoma, we first divided osteosarcoma patients into two groups, MAT1 high expression group (n = 24) and MAT1 low expression group (n = 23), according to the expression levels of MAT1 obtained from immunohistochemistry staining of MAT1. The results showed that the high expression level of MAT1 closely associated with advanced clinical stage (P = 0.013) and high incidence of lung metastasis (P = 0.002) (Table 1), suggesting that MAT1
Discussion
Human MAT1 gene (ménage trois 1) is located in chromosome 14q23 and codes a 37 kDa-protein that can activates cyclin-associated kinases through threonine phosphorylation [21]. In the present study, we aimed to explore the effects of MAT1 on the lung metastasis of osteosarcoma. The results reveal that MAT1 servers as an inducer of the lung metastasis in osteosarcoma. Our findings may provide a potent therapeutic target of MAT1 for the lung metastasis of osteosarcoma.
Through immunohistochemical
Conclusion
In conclusion, this study clarifies that MAT1 facilitates the lung metastasis of osteosarcoma through increasing AKT1 expression both in vivo and in vitro. Our study provides theoretical basis for serving MAT1 as a new target for preventing and treating osteosarcoma lung metastasis.
Acknowledgements
This study was supported by the Grant of Xiangya famous doctors of Central South University.
Declaration of competing interest
The authors declare that there is no any form of interest conflict.
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