Mithramycin Inhibits Epithelial-to-mesenchymal Transition And Invasion By Downregulating Sp1 And Snail In Salivary Adenoid Cystic Carcinoma

Salivary adenoid cystic carcinoma(SACC)is a rare malignant neoplasm,representing approximately 30%of human salivary gland malignancies,that arises from secretory epithelial cells of salivary glands.The biological properties of SACC include slow local growth,high incidences of nerve and blood vessel invasion,infrequent regional metastases and frequent local recurrence,poor long-term prognosis and relatively indolent distant metastases.Surgical resection is still the primary method for treating SACC,and postoperative radiotherapy is necessary to kill remaining cancer cells and prevent distant metastases.Despite recent advances in surgery and adjuvant therapy,the overall 10-year survival and incidence of tumour recurrence in SACC patients have not significantly improved.Therefore,there is a pressing need to identify anti-metastatic drugs for SACC.Mithramycin was evaluated as a chemotherapeutic agent in patients with a variety of malignancies.Later studies showed that mithramycin specifically inhibits the binding of specificity protein 1(SP1)to GC-rich DNA,which results in the repression of numerous genes that mediate proliferation,invasion and metastasis.The SP1 zinc-finger transcription factor binds to GC-rich motifs and regulates various physiologic processes.SP1 is overexpressed and contributes to the tumorigenic phenotype in various human cancers by upregulating genes that induce proliferation,invasion and metastasis.In this study,we examined the effects on mithramycin on SACC and explored the potential mechanism.For the first time,we show that mithramycin effectively inhibited EMT by inducing SP1 in human salivary adenoid cystic carcinoma in vitro and vivo.In vitro,we found that mithramycin significantly inhibited proliferation,migration,invasion and EMT and promoted apoptosis in human SACC cell lines in a dose-dependent manner.We also investigated EMT-and invasion-associated markers,and the results showed that N-cadherin,Vimentin and MMP-2 expression were decreased,while E-cadherin was increased after treating SACC-LM and SACC-83 cell lines with mithramycin.Moreover,in vivo our studies indicated that mithramycin could decrease the volume and weight of xenograft tumors and significantly decrease the expression of EMT markers in SACC tissues.Therefore,our results provide a novel insight,suggesting that mithramycin be a new choice for treating SACC.