Knockdown of the prognostic cancer stem cell marker Musashi-1 decreases radio-resistance while enhancing apoptosis in hormone receptor-positive breast cancer cells via p21 WAF1/CIP1

• Published in: Journal of cancer research and clinical oncology 2021-11, Vol.147 (11), p.3299
• Main Authors: Troschel, Fabian M, Palenta, Heike, Borrmann, Katrin, Heshe, Kristin, Hua, San Hue, Yip, George W, Kiesel, Ludwig, Eich, Hans Theodor, Götte, Martin, Greve, Burkhard
• Format: Article
• Language: English
• Subjects: Aged; Apoptosis - physiology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - radiotherapy; Cell Proliferation - physiology; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Down-Regulation; Female; Gene Knockdown Techniques; Humans; MCF-7 Cells; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - radiation effects; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Prognosis; Radiation Tolerance; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism
• ISSN: 1432-1335
• DOI: 10.1007/s00432-021-03743-y

While the stem cell marker Musashi-1 (MSI-1) has been identified as a key player in a wide array of malignancies, few findings exist on its prognostic relevance and relevance for cancer cell death and therapy resistance in breast cancer. First, we determined prognostic relevance of MSI-1 in database analyses regarding multiple survival outcomes. To substantiate findings, MSI-1 was artificially downregulated in MCF-7 breast cancer cells and implications for cancer stem cell markers, cell apoptosis and apoptosis regulator p21, proliferation and radiation response were analyzed via flow cytometry and colony formation. Radiation-induced p21 expression changes were investigated using a dataset containing patient samples obtained before and after irradiation and own in vitro experiments. MSI-1 is a negative prognostic marker for disease-free and distant metastasis-free survival in breast cancer and tends to negatively influence overall survival. MSI-1 knockdown downregulated stem cell gene expression and proliferation, but increased p21 levels and apoptosis. Similar to the MSI-1 knockdown effect, p21 expression was strongly increased after irradiation and was expressed at even higher levels in MSI-1 knockdown cells after irradiation. Finally, combined use of MSI-1 silencing and irradiation reduced cancer cell survival. MSI-1 is a prognostic marker in breast cancer. MSI-1 silencing downregulates proliferation while increasing apoptosis. The anti-proliferation mediator p21 was upregulated independently after both MSI-1 knockdown and irradiation and even more after both treatments combined, suggesting synergistic potential. Radio-sensitization effects after combining radiation and MSI-1 knockdown underline the potential of MSI-1 as a therapeutic target.