<p>A Chemotherapy-Driven Increase in Mcl-1 Mediates the Effect of miR-375 on Cisplatin Resistance in Osteosarcoma Cells</p>

Abstract

Background: Osteosarcoma (OS) is one of the most difficult cancers to treat due to its resistance to chemotherapy. The essential role played by Mcl-1 in promoting chemoresistance has been observed in a variety of cancers, including OS, while the underlying mechanism remains unclear. Methods: We investigated the expression of Mcl-1 in 42 paired OS specimens obtained before and after adjuvant chemotherapy, and its correlation with clinicopathological characteristics. Loss and gain of function studies were performed to analyze the effects of Mcl-1 modulations on the chemosensitivity, and the mechanism involved in the deregulation of Mcl-1 in OS cells. Results: In OS specimens, the expression of Mcl-1 was significantly upregulated after chemotherapy, and high Mcl-1 expression was associated with poorer overall survival and an increased recurrence rate. Furthermore, we demonstrated that chemotherapy-driven increased Mcl-1 decreased chemosensitivity by promoting tumour proliferation and inhibiting DNA damage. Moreover, Mcl-1 was found to be a direct target of miR-375 in OS cells. The knockdown of Mcl-1 phenocopied miR-375 downregulation, and the overexpression of miR-375 rescued the effects of cisplatin-induced DNA damage mediated by Mcl-1. Conclusion: Our data indicated that chemotherapy-driven increase in the expression of Mcl-1 plays a critical role in chemoresistance, and the intervention of the miR-375/Mcl-1 axis may offer a novel strategy to enhance chemosensitivity in OS treatment.

An overview of resistance to chemotherapy in osteosarcoma and future perspectives

“…Abemaciclib combined with DOX results in much greater efficacy than DOX alone in inhibiting tumor growth; it acts by suppressing the CD4/6-Cyclin D-Rb pathway. A clinical trial with OS and abemaciclib is ongoing (NCT04040205) [52,53] .…”

“…Inhibition of BCL1/BCLXL enhanced the chemosensitivity of OS to DOX and cisplatin. Myeloid cell leukemia-1 (MCL-1) is a pro-survival member of the BCL2 family, contributing to the avoidance of cell death by acting as a regulator of apoptosis in some human malignancies [ 54 ] . In OS, MCL-1 expression is upregulated after chemotherapy, and high MCL-1 expression is associated with poor overall survival, increased recurrence rate, decreased sensitivity to MTX, and promotion of tumor proliferation [ 55 ] .…”

“…In OS, MCL-1 expression is upregulated after chemotherapy, and high MCL-1 expression is associated with poor overall survival, increased recurrence rate, decreased sensitivity to MTX, and promotion of tumor proliferation [ 55 ] . In OS cells, MCL-1 is a direct target of miR-375; overexpression of miR-375 enhances the effects of cisplatin-induced DNA damage mediated by MCL-1 [ 54 ] . Regorafenib is an oral type II multikinase inhibitor that inhibits the vascular endothelial growth factor receptor 1-3 (VEGFR1-3), platelet-derived growth factor receptors, fibroblast growth factor receptors (FGFR), tyrosine kinase receptor with immunoglobulin-like and EGFR-like domains 2 (TIE-2), and pathways involved in angiogenic and metastasis process.…”

MicroRNAs as Guardians of the Prostate: Those Who Stand before Cancer. What Do We Really Know about the Role of microRNAs in Prostate Biology?

“…For example, massive un-physiological overexpression of miR-375 may “always” result in a growth-suppressive phenotype in vitro in prostate cancer cells or for that matter any cancer cell (e.g., oral cancer). To explore this issue in a more unbiased fashion and shed light on the unsatisfactory conclusions about miR-375’s role in cancer, we selected ten of the most recent publications [ 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ] and ten of the most cited publications [ 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ] that deal with miR-375 and determined the pro- or anti-growth outcomes of its overexpression or inhibition in these studies. Overexpression using a miR-375 mimic produced growth inhibition and/or induction of apoptosis in 16 of the 17 studies, while miR-375 inhibition had either no effect or mild pro-growth effects in 7 of 10 studies.…”

“…Even almost complete inhibition of miR-375 had almost no effect on the cells in vitro [ 99 ]. Only three studies (two on breast cancer cell lines MDA-MB231 and MCF7 and one on miR375 knockout in mouse pancreas) indicate an oncogenic or at least pro-growth effect of miR-375 [ 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ].…”