MicroRNA-944 Inhibits Breast Cancer Cell Proliferation And Promotes Cell Apoptosis By Reducing SPP1 Through Inactivating The PI3K/AKt Pathway

Objective: Breast cancer is a frequently occurring malignancy among women on a global scale and contributes to cancer-related mortality.Genetic alterations and intracellular pathways can affect carcinogenesis,and oncogenes have been linked with the development of cancers including breast cancer.Therefore,it is of significance to seek novel gene targets for treatment of breast cancer.It should be worthy to note that secreted phosphoprotein-1(SPP1),also known as osteopontin,is a multifunctional protein expressed in multiple cell types;SPP1 can function in intercellular communication and in extracellular matrix.The phosphoinositide3-kinase(PI3K)/Akt signaling pathway is a crucial node in mammalian cells modulating cell behaviors such as growth and metabolism,migration and proliferation.Repression of PI3K/Akt signaling by SPP1 knockdown could aid in suppressing migration and invasion of breast cancer cells while enhancing the apoptosis.Following upstream miRNA prediction,we identified miR-944 as the key miRNA.miR-944 is aberrantly expressed in more than 10 cancers and implicated in PI3K/Akt pathway.Specifically,poor miR-944 expression was detected in breast cancer cell lines and tissues.Importantly,miRNAs exert diverse function in diseases and cancers via targeting m RNA.Considering the above reports,a hypothesis was thus proposed in the present study that miR-944 might target and regulate SPP1 to affect the progression of breast cancer with the involvement of the PI3K/Akt pathway,and a series of experiments were conducted to testify it.Methods: 1.Differential gene analysis was performed to identify key genes associated with breast cancer development by screening breast cancer-related microarray data.2.The expression of miR-944 and SPP1 and their relationship were determined in clinical samples and cells.By MCF-7 cells to investigate the role of miR-944 mediated SPP1 in breast cancer development and its regulatory effect on the PI3K/Akt pathway.3.The tumorigenicity of breast cancer cells was observed in nude mice.Results: 1.Through bioinformatics analysis,we identified SPP1 as a key gene in breast cancer,and miR-944 as an upstream miRNA of SPP1.2.In breast cancer tissues and cells,the expression of miR-944 was decreased while that of SPP1 was increased.miR-944 negatively regulated the expression of SPP1.In breast cancer cells,SPP1 activated the PI3K/Akt pathway to promote cell proliferation and inhibit apoptosis.In vitro cell experiments showed that the downregulation of miR-944 promoted the high expression of SPP1,which then activated the PI3K/Akt signaling pathway,promoting breast cancer cell proliferation.3.In vivo experiments further confirmed the anti-cancer role of miR-944 mediated SPP1 in breast cancer.Our study highlights the role of miR-944 mediated SPP1 in inhibiting breast cancer progression by blocking the PI3K/Akt pathway.Conclusion: 1.Through bioinformatics analysis,we identified SPP1 as a key gene in breast cancer.2.Knockdown of SPP1 inhibited breast cancer cell proliferation and promoted cell apoptosis.3.SPP1 activated the PI3K/Akt pathway to promote breast cancer cell proliferation and inhibit cell apoptosis.4.miR-944 may be the upstream miRNA of SPP1.5.miR-944 regulated SPP1/PI3K/AKT pathway to inhibit the activity of breast cancer cells and tumorigenesis of breast cancer cells in vivo.