CSN6 promotes malignant progression of oral squamous cell carcinoma by down-regulating TIMP-2.

W-Y Gao, G Yang, J Wang, J-M He, P Wang

European review for medical and pharmacological sciences 2020 May

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This study was designed to investigate the expression characteristics of CSN6 in oral squamous cell carcinoma (OSCC), and to further explore the mechanism of how it promotes the malignant progression of this cancer. The expressions of CSN6 and TIMP-2 in tumor tissue samples and adjacent normal ones collected from 36 OSCC patients were detected via quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), and the interplay between their expression levels and the clinical indicators or prognosis of OSCC patients was analyzed as well. Meanwhile, the expressions of CSN6 and TIMP-2 in OSCC cell lines were further verified via qRT-PCR. In addition, CSN6 overexpression and knockdown models were constructed using lentivirus in OSCC cell lines, CAL-27, and Tca8113. At the same time, transwell and cell wound healing assays were conducted to uncover the impact of CSN6 on the function of OSCC cells. Finally, the potential mechanism was explored using Luciferase reporter gene and recovery experiments. In this work, qRT-PCR results revealed that the level of CSN6 in tumor tissues of OSCC patients was remarkably higher than that in adjacent normal ones. Compared with patients with low expression of CSN6, those with high expression CSN6 had a higher incidence of lymph node or distant metastasis and a lower overall survival rate. In vitro experiments revealed that silencing CSN6 remarkably attenuated the invasive, as well as migration capacities of OSCC cells while overexpression of CSN6 conversely enhanced those. Subsequently, in OSCC cell lines and tissues, TIMP-2 expression was remarkably reduced, which was negatively correlated with CSN6 level. Bioinformatics and Luciferase reporter genes demonstrated that CSN6 can target the corresponding sites of TIMP-2 promoter. In addition, cell recovery experiments suggested the existence of a mutual regulation between CSN6 and TIMP-2, which may synergistically modulate the malignant progression of OSCC. The above results indicated that CSN6 was remarkably upregulated both in OSCC tissues and cell lines, which is remarkably relevant to the incidence of lymph node or distant metastasis and poor prognosis of OSCC patients. Additionally, we verified that CSN6 may promote OSCC malignant progression by regulating TIMP-2.

Citation

W-Y Gao, G Yang, J Wang, J-M He, P Wang. CSN6 promotes malignant progression of oral squamous cell carcinoma by down-regulating TIMP-2. European review for medical and pharmacological sciences. 2020 May;24(10):5419-5428