Sox4 Exhibits Pro-oncogenic Activity By Activating The Wnt7a/Akt/mTOR Pathway In Salivary Adenoid Cystic Carcinoma

Research background:Salivary adenoid cystic carcinoma(SACC)is a rare malignant neoplasm that arises from secretory epithelial cells of salivary glands.It represents approximately 30%of human salivary gland malignancies.The biological properties of SACC include slow local growth,a high incidence of nerve and blood vessel invasion,infrequent regional metastases and frequent local recurrence,poor long-term prognosis and relatively indolent distant metastasis.Despite recent advances in surgery and adjuvant therapy,the overall 10-year survival and tumour recurrence in SACC patients have not significantly improved.Therefore,understanding the molecular mechanism underlying the development and progression of SACC is crucial for developing novel and effective therapeutic strategies.Sox4 is a member of the Sox(SRY-related HMG-box)family of transcription factors and has an essential role in embryonic development and lymphocyte differentiation.Previous studies indicated that Sox4 plays an important role in the formation and progression of different types of cancers,such as medulloblastoma,small cell lung cancer,prostate cancer and breast cancer.However,its exact role in tumour progression is unclear and has shown certain contradictions in different cancers.For example,high Sox4expression is associated with better prognosis for patients with glioblastoma multiforme but shorter survival in breast cancer patients.In this study,Sox4 expression in SACC tissues was measured relative to adjacent non-cancerous salivary gland tissues.The inhibition of Sox4 induced apoptosis and suppressed cell proliferation,invasion and migration in SACC cell lines.Moreover,we further showed that Sox4,a tumour oncogene in SACC,was mediated by activating the Wnt7a/Akt/mTOR pathway.Methods:1?The expression of Sox4 in the salivary adenoid cystic carcinoma tissues?Oncomine database was used to detect the expression of Sox4 in salivary adenoid cystic carcinoma.? Western-blot was used to measure the expreesion of Sox4 in 5 human clinical SACC tissue samples.2?Effect of Sox4 on SACC cells proliferation siRNA-mediated knockdown of Sox4 was employed in SACC-M and SACC-83 cells.both siRNAs targeting Sox4(siRNAl and siRNA2)efficiently reduced Sox4 expression in the SACC-83 and SACC-M cells compared with the negative control(NC),as shown by real-time RT-PCR and Western-blot,then CCK8 and colony formation assays verify the correlation between Sox4 knockdown and SACC cell proliferation.3?Effect of Sox4 on SACC cells invasion and migration ability and apoptosis process siRNA-mediated knockdown of Sox4,Wound healing assay and Cell invasion assay were used to detect the effect of Sox4 on SACC cell invasion and migration ability;then Annexin V-FITC and PI double staining were used to detect and quantify cellular apoptosis.4?The molecular mechanism of Sox4 regulating SACC cells Western-blot analysis the protein levels of the Sox4 target gene decreased in the Sox4 siRNAl group and NC group in Sox4-siRNA SACC-83 and SACC-M.Results:Sox4 was highly upregulated in salivary adenoid cystic carcinoma tissuesInhibition of Sox4 decreases SACC cells proliferationInhibition of Sox4 suppresses migration and invasion and induces apoptosis of SACC cellsInhibition of Sox4 reduces the activation of the Wnt7a/Akt/mTOR pathwayConclusions:Sox4 is over-expressed in salivary adenoid cystic carcinoma tissuesInhibition of Sox4 decreases SACC cells proliferation,migration and invasion,at the same time induces apoptosis of SACC cellsInhibition of Sox4 reduces the activation of the Wnt7a/Akt/mTOR pathway.The Wnt7a/Akt/mTOR pathway plays an important role in regulating the process in salivary adenoid cystic carcinoma.