The Mechanism Research Of Sphingomyelin Synthase 2(SGMS2)on Promoting Metastasis Of Breast Cancer Through TGF-?/Smad Signaling Pathway

Background and ObjectiveBreast Cancer is the most frequently diagnosed cancer in females worldwide.As a serious threat to women's physical and mental health,breast cancer is one of the main causes of cancer death in women.Although surgery,chemotherapy,radiotherapy and other comprehensive treatments are effective for it,breast cancer still has substantial risk of recurrence and metastasis while metastasis is the major cause of mortality in patients.The detailed mechanism of tumor metastasis is not yet illustrated.It is of great significant to further understand the mechanism of breast cancer metastasis.Sphingomyelin synthase 2(SGMS2),locating on the cell membrane,catalyzes the synthesis of sphingomyelin(SM)and diglyceride with ceramide and lecithin as substrates.Ceramide and sphingomyelin are important lipid components of cell,which are closely related to the development of malignant tumors.As a key enzyme to maintain the celluar homeostasis of ceramide and sphingomyelin,SGMS2 has not been clearly and detailed reported about its role in the development and progression of tumors.And little is known about the influence of SGMS2 on breast cancer metastasis and related molecular mechanisms.Our preliminary study have found that SGMS2 can inhibit cell apoptosis and enhance cell proliferation via Cer related signal pathway.Therefore,this study was designed to further illustrate the role of SGMS2 in promoting the occurrence of metastasis in breast cancer from the perspective of cell lipid metabolism,so as to provide a new scientific basis for the research and clinical therapy of metastasis in breast cancer.Merhods1.Through statistical analysis of GEO database data,the expression differences of SGMS2 in metastatic breast cancer and non-metastatic breast cancer samples were determined.Real-time PCR was used to detect the mRNA level of SGMS2 in clinicopathological samples of non-metastatic breast cancer and breast cancer tissues.2.MCF-7 and MDA-MB-231 cells were selected to construct breast cancer cell lines that overexpressed SGMS2 or interfered with SGMS2 expression.3.The effects of SGMS2 on migration,invasion and metastasis of breast cancer cells were verified by wound healing assay,Transwell assay and nude mice tail vein lung metastasis model.4.Cell immunofluorescence and Western Blot were used to observe the effect of SGMS2 on EMT in breast cancer cells and related signalling pathways.5.Western Blot and ELISA were used to further explore the mechanism underlying the activation of TGF-?/Smad signalling pathway mediated by SGMS2 in breast cancer cells.Results1.There was no significant difference in SGMS2 expression between breast cancer and para-carcinoma tissue.SGMS2 expression was significantly increased in breast cancer tissues from patients with metastasis.2.Overexpression of SGMS2 significantly enhanced the migration and invasion ability of breast cancer cells while interference in SGMS2 expression resulted in the opposite.3.SGMS2 promoted the EMT process in breast cancer cells by activating the TGF-?/Smad signaling pathway.4.Specific blocking of the TGF-?/Smad signaling pathway reversed the SGMS2-mediated alteration in EMT.5.SGMS2 overexpression activated the TGF-?/Smad signaling pathway by promoting the transcription and secretion of TGF-? 1.This may be related to the promotion of SM synthesis by SGMS2.Interfering with SGMS2 expression resulted in the opposite.ConclusionsSGMS2 expression was increased in metastatic breast cancer.SGMS2 increased the transcription and secretion of TGF-? 1,which subsequently activated the TGF-?/Smad signalling pathway and promoted EMT in breast cancer cells,thus increasing the migration and invasiveness of breast cancer cells.Here,we demonstrated that SGMS2 may form the conceptual basis of a novel targeted therapies for breast cancer metastasis.