miR‐15b modulates multidrug resistance in human osteosarcoma in vitro and in vivo

Abstract

The development of multidrug resistance (MDR) in cancer cells to chemotherapy drugs continues to be a major clinical problem. MicroRNAs (miRNA, miR) play an important role in regulating tumor cell growth and survival; however, the role of miRs in the development of drug resistance in osteosarcoma cells is largely uncharacterized. We sought to identify and characterize human miRs that act as key regulators of MDR in osteosarcoma. We utilized a miR microarray to screen for differentially expressed miRs in osteosarcoma MDR cell lines. We determined the mechanisms of the deregulation of expression of miR-15b in osteosarcoma MDR cell lines, and its association with clinically obtained tumor samples was examined in tissue microarray (TMA). The significance of miR-15b in reversing drug resistance was evaluated in a xenograft mouse model of MDR osteosarcoma. We identified miR-15b as being significantly (p<0.01) downregulated in KHOSMR and U-2OSMR cell lines as compared with their parental cell lines. We found that Wee1 is a target gene of miR-15b and observed that transfection of miR-15b inhibits Wee1 expression and partially reverses MDR in osteosarcoma cell lines. Systemic in vivo administration of miR-15b mimics sensitizes resistant cells to doxorubicin and induces cell death in MDR models of osteosarcoma. Clinically, reduced miR-15b expression was associated with poor patient survival. Osteosarcoma patients with low miR-15b expression levels had significantly shorter survival times than patients with high expression levels of miR-15b. These results collectively indicate that MDR in osteosarcoma is associated with downregulation of miR-15b, and miR-15b reconstitution can reverse chemotherapy resistance in osteosarcoma.

miR‐15b‐5p facilitates the tumorigenicity by targeting RECK and predicts tumour recurrence in prostate cancer

“…Aberrant regulation of miR-15b plays a key role in cell proliferation, angiogenesis and metastasis in a variety of tumours [26]. According to the previous studies, miR-15b has displayed decreased expression [6][7][8][9][10][11][12] or increased expression [17][18][19][20][21] in human tumours. Even, miR-15b harbours the opposite expression levels in the same tumour tissues, such as glioma [7,18], indicating that its expression level is related with the specific types of tumour tissues.…”

Small animal models for the study of bone sarcoma pathogenesis:characteristics, therapeutic interests and limitations

“…Cancer cells have been also incorporated into acellular Matrigel™ based-matrix to provide an active bio-molecule scaffold from murine origin and facilitate cell engraftment. Utilising such an approach, Duan et al established osteosarcoma tumours subcutaneously by resuspending KHOS osteosarcoma cells in a 1:1 Matrigel™ volume ratio and injected an amount of 2 × 10 6 cells per mouse [8] . The use of the Saos-2 human osteosarcoma cells combined with Matrigel™ was also reported.…”

Influence mechanism of miRNA‑144 on proliferation and apoptosis of osteosarcoma cells

“…After 24 h of transfection, the cells were collected and adjusted to 4x10 6 cells. The cells were diluted into a cell suspension of 5x10 5 cells/ml and 100 µl of the cells were collected and inoculated into a 96-well plate.…”

“…At present, researchers world-wide are striving to explore the possible serum markers in osteosarcoma (3)(4)(5), but still have not made a significant breakthrough. Studies have pointed out that the median survival time of patients with advanced osteosarcoma is only ~20 months (6). Therefore, in-depth understanding of osteosarcoma and the search for potential diagnostic targets are currently under intense investigations (7,8).…”