Roles of microRNA‐22 in Suppressing Proliferation and Promoting Sensitivity of Osteosarcoma Cells <i>via</i> Metadherin‐mediated Autophagy

Wang, Peng; Zhao, Zhenqun; Guo, Sisi; Yang, Tieyi; Chang, Zhiqiang; Daihe, Li; Zhao, Wei; Wang, Yuxin; Sun, Chao; Wang, Yong; Feng, Wei

doi:10.1111/os.12442

Cited by 26 publications

(20 citation statements)

References 42 publications

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“…in the present study, the autophagy-related genes, aTG5, beclin1 and lc3, were downregulated by mir-22 overexpression in MG-63/cddP cells, which was consistent with the conclusions drawn from a previous study, which reported that mir-22 decreased the expression of aTG5, beclin1 and lc3 in MG-63 cells (22). The present study further verified that miR-22 could reduce cddP resistance by inhibiting autophagy.…”

Section: Mir-22 Inhibits the Proliferation Of Mg-63 Cells And Mg-63/csupporting

confidence: 93%

MicroRNA‑22 regulates autophagy and apoptosis in cisplatin resistance of osteosarcoma

et al. 2020

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osteosarcoma (oS) is a primary malignant tumor of bone tissue. effective chemotherapy may improve the survival of patients with OS. MicroRNAs (miRs) serve significant roles in the regulatory function of tumorigenesis and chemosensitivity of different types of cancer. mir-22 has been revealed to inhibit the proliferation and migration of oS cells, as well as increasing their sensitivity to cisplatin (cddP). The mechanisms of action behind the functions of mir-22 in oS drug resistance require investigation. Therefore, in the present study, the human oS cell lines (MG-63, u2oS, Saos2 and oS9901) and a drug-resistant cell line (MG-63/cddP) were cultured. cell proliferation, apoptosis and autophagy assays were performed to investigate the proliferation, apoptosis and autophagy of cell lines transfected with mir-22 mimic. reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to investigate the expression levels of associated genes. The results revealed that mir-22 inhibited the proliferation of MG-63 cells and MG-63/cddP cells, and enhanced the anti-proliferative ability of cddP. mir-22 induced apoptosis and inhibited autophagy of MG-63 cells and MG-63/cddP cells. apoptosis-related genes, including caspase-3 and Bcl-2-associated X protein were upregulated, while B-cell lymphoma-2 was downregulated in both cell lines transfected with the mir-22 mimic. autophagy protein 5, beclin1 and microtubules-associated protein 1 light chain 3 were downregulated in both cell lines transfected with mir-22 mimic. Furthermore, the in vitro and in vivo expression levels of metadherin (MTdH) in the oS/oS-cddP-resistant models were downregulated following transfection with the mir-22 mimic. Therefore, the results of the present study suggested that mir-22 promoted cddP sensitivity by inhibiting autophagy and inducing apoptosis in oS cells, while MTdH may serve a positive role in inducing cddP resistance of oS cells.

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Section: Mir-22 Inhibits the Proliferation Of Mg-63 Cells And Mg-63/csupporting

confidence: 93%

MicroRNA‑22 regulates autophagy and apoptosis in cisplatin resistance of osteosarcoma

et al. 2020

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“…In addition, expression of LC3 is associated with autophagy. Moreover, the results consolidated to findings which were obtained by measuring LC3B II/LC3B I, MDC staining and electron microscopy observation (25,31). Thus, we performed LC3 flow cytometry to verify autophagy.…”

Section: Mir-22 Suppresses Autophagy Of the Mg63 And Mg63/cddp Cell Lsupporting

confidence: 71%

“…It was previously reported that miR-22 targets the gene HMGB1 to suppress autophagy, leading to a reduction in the levels of adriamycin and CDDP resistance (23,24). Another recently published study demonstrated that miR-22 suppressed the proliferation, and promote the sensitivity, of OS cells via metadherin (MTDH)-mediated autophagy (25). The PI3K/Akt/mTOR pathway is an important pathway that regulates autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we mainly argued that CDDP could increase the autophagy of MG63 cells and the expression of autophagy-related genes including microtubule-associated protein 1 light chain 3 (LC3), autophagy related 5 (ATG5) and Beclin-1 (BECN1) and miR-22 could inhibit the upregulation of those genes induced by CDDP. However, the specific pathway associated with miR-22 and the effect of miR-22 on MG63 and CDDP-resistant cells still need to be investigated (25). In addition, only a few studies have focused attention on the pathway that is influenced by miR-22 in OS.…”

Section: Microrna-22 Mediates the Cisplatin Resistance Of Osteosarcommentioning

confidence: 99%

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MicroRNA‑22 mediates the cisplatin resistance of osteosarcoma cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway

et al. 2020

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Osteosarcoma (OS) is the most common primary malignant tumor of the bone affecting children and adolescents. Chemotherapy is now considered as a standard component of OS treatment, not only for children, but also for adults. However, chemoresistance continues to pose a challenge to therapy. Inhibition of autophagy has been demonstrated to decrease chemoresistance in OS. Moreover, microRNA-22 (miR-22) inhibits autophagy, leading to an improvement in the sensitivity of cisplatin (CDDP) in OS. The aim of the present study was therefore to investigate whether miR-22 could mediate the CDDP resistance of OS cells by inhibiting autophagy via the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Cell proliferation assay, LC3 flow cytometry assay and monodansylcadaverine staining in MG63 cells and CDDP resistance cells (MG63/CDDP) were performed to explore to role of miR-22 and CDDP in OS chemoresistance. Inoculation of tumor cells in an in vivo model, reverse transcription-quantitative PCR (RT-qPCR) assay, western blot analysis, and immunohistochemistry analysis were performed to investigate the role of miR-22 and CDDP in the PI3K/Akt/mTOR pathway as it is affected by autophagy. The results revealed that miR-22 inhibited the proliferation of MG63 and MG63/CDDP cells, and enhanced the anti-proliferative ability of CDDP in vivo and in vitro. miR-22 mediated the CDDP resistance of OS cells by inhibiting autophagy and decreasing CDDP-induced autophagy via downregulation of the expression of PI3K, Akt, and mTOR at the mRNA level, and the expression of PI3K, phosphorylated (p)-Akt, and p-mTOR at the protein level. It was also convincingly demonstrated that miR-22 mediates the CDDP resistance of OS by inhibiting autophagy via the PI3K/Akt/mTOR pathway. Furthermore, in the MG63 cells that were affected by CDDP, the role of miR-22 was shown to be similar to that of the investigated inhibitor of PI3K (wortmannin) in terms of regulating the PI3K/Akt/mTOR pathway, and wortmannin could also promote the effect of miR-22. Interestingly, CDDP was demonstrated to induce autophagy by inhibiting the PI3K/Akt/mTOR pathway, whereas the pathway was upregulated in the state of chemoresistance. In conclusion, downregulation of the PI3K/Akt/mTOR pathway was shown to assist in the process of preventing chemoresistance.

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“…The loss of cartilage cells, osteocyte, and osteoblasts is hypothesized to drive SANFH, although the type of cell death is not completely clear. Autophagy is an auto‐catabolic recycling process of eukaryotic cells that is frequently dysregulated in cancer, inflammatory diseases, autoimmune diseases, aging, etc. Our preliminary results show that SANFH is associated with autophagy, and the autophagy‐related Beclin 1 and microtubule‐associated protein 1 light chain 3 (MAP1LC3) are upregulated in osteoblasts.…”

Section: Introductionmentioning

confidence: 75%

Mechanism of Methylprednisolone‐Induced Primary Cilia Formation Disorder and Autophagy in Osteoblasts

Zhao

Liu

Guo

et al. 2020

Orthopaedic Surgery

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Objective: To study the role of primary cilia formation disorder and osteoblasts autophagy in the pathogenesis of steroid-induced avascular necrosis of the femoral head (SANFH).Methods: Osteoblasts were isolated from rabbit bones and treated with 1 μM Methylprednisolone for 0, 12, 24, 48, and 72 h. The Beclin1, MAP1LC3, Atg-5, Atg-12, IFT20 and OFD1 mRNAs and proteins were detected by PCR and Western blotting, and their correlation was statistically analyzed. The lengths of osteoblast cilia were measured under a laser confocal microscope, and the autophagy flux was tracked by transfecting the osteoblasts with GFP-RFP-LC3 lentivirus.Results: Methylprednisolone significantly upregulated Beclin1, MAP1LC3, Atg-5, Atg-12 and OFD1 mRNAs and proteins in a time-dependent manner, and decreased that of IFT20 (P < 0.05). In addition, the autophagy flux in the osteoblasts also increased and the ciliary length decreased in a time-dependent manner after Methylprednisolone treatment. The length of the cilia were 5.46 AE 0.11 um at 0 h, 4.08 AE 0.09 um at 12 h, 3.07 AE 0.07 um at 24 h, 2.31 AE 0.10 um at 48 h, and finally 1.15 AE 0.04 um at 72 h. Methylprednisolone treatment also affects primary cilium numbers in cultures, for 0 to 72 h. The autophagy regulatory genes, Beclin1, MAP1LC3, Atg-5 and Atg-12, were found to be negatively correlated with IFT20, with an average correlation coefficient of −0.81. A negative correlation was also found between OFD1 and IFT20, with an average correlation coefficient of −0.53. Conclusion:Methylprednisolone inhibits primary cilia formation and promotes autophagy, which could be the pathological basis of SANFH. The exact regulatory mechanism needs to be further studied in vivo.

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Roles of microRNA‐22 in Suppressing Proliferation and Promoting Sensitivity of Osteosarcoma Cells via Metadherin‐mediated Autophagy

Cited by 26 publications

References 42 publications

MicroRNA‑22 regulates autophagy and apoptosis in cisplatin resistance of osteosarcoma

MicroRNA‑22 regulates autophagy and apoptosis in cisplatin resistance of osteosarcoma

MicroRNA‑22 mediates the cisplatin resistance of osteosarcoma cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway

Mechanism of Methylprednisolone‐Induced Primary Cilia Formation Disorder and Autophagy in Osteoblasts

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