Dataset Information

LncRNA Sox2OT-V7 promotes doxorubicin-induced autophagy and chemoresistance in osteosarcoma via tumor-suppressive miR-142/miR-22.

ABSTRACT: Doxorubicin (Dox) is one of the most commonly used chemotherapeutic drugs for osteosarcoma (OS) treatment. In the present study, we attempted to investigate the mechanism by which Sox2OT-V7 dysregulation affects Dox chemoresistance to provide a novel experimental basis for developing neoadjuvant therapy. Sox2OT-V7 expression is upregulated in OS tissues, particularly in chemoresistant OS tissues, and in OS cell lines compared to controls. Dox treatment induces autophagy and Sox2OT-V7 expression in U2OS cells, and Dox-induced autophagy is partially attenuated by Sox2OT-V7 silencing. Knocking down Sox2OT-V7 or blocking autophagy in Dox-resistant U2OS/Dox cells resensitizes the cells to Dox treatment in vitro. Moreover, Sox2OT-V7 directly targets miR-142/miR-22 to inhibit their expression, and the effect of Sox2OT-V7 silencing on U2OS cell autophagy and U2OS/Dox cell sensitivity to Dox can be reversed by miR-142/miR-22 inhibition. Sox2OT-V7 silencing enhances the suppressive effects of Dox on U2OS/Dox cell-derived tumor growth in vivo, while miR-22 inhibition or miR-142 inhibition reverses the effects of Sox2OT-V7 silencing on Dox-induced suppression on tumor growth. Finally, miR-142 directly targets ULK1, ATG4A, and ATG5, while miR-22 directly targets ULK1 to inhibit the expression of the target gene; The Sox2OT-V7/miR-142/miR-22 axis modulates autophagy in OS cells by regulating ULK1, ATG4A, and ATG5.

SUBMITTER: Zhu K

PROVIDER: S-EPMC7202483 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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LncRNA Sox2OT-V7 promotes doxorubicin-induced autophagy and chemoresistance in osteosarcoma via tumor-suppressive miR-142/miR-22.

Zhu Kewei K Yuan Yang Y Wen Jie J Chen Ding D Zhu Weihong W Ouyang Zhengxiao Z Wang Wanchun W

Aging 20200416 8

Doxorubicin (Dox) is one of the most commonly used chemotherapeutic drugs for osteosarcoma (OS) treatment. In the present study, we attempted to investigate the mechanism by which Sox2OT-V7 dysregulation affects Dox chemoresistance to provide a novel experimental basis for developing neoadjuvant therapy. Sox2OT-V7 expression is upregulated in OS tissues, particularly in chemoresistant OS tissues, and in OS cell lines compared to controls. Dox treatment induces autophagy and Sox2OT-V7 expression ...[more]

PMID: 32302291

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Project description:Translational control mediated by non-coding microRNAs (miRNAs) plays a key role in the mechanism of cellular resistance to anti-cancer drug treatment. Dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS, TS) are two of the most important targets for antifolate- and fluoropyrimidine-based chemotherapies in the past 50 years. In this study, we investigated the roles of miR-215 in the chemoresistance to DHFR inhibitor methotrexate (MTX) and TS inhibitor Tomudex (TDX).The protein levels of both DHFR and TS were suppressed by miR-215 without the alteration of the target mRNA transcript levels. Interestingly, despite the down-regulation of DHFR and TS proteins, ectopic expression of miR-215 resulted in a decreased sensitivity to MTX and TDX. Paradoxically, gene-specific small-interfering RNAs (siRNAs) against DHFR or TS had the opposite effect, increasing sensitivity to MTX and TDX. Further studies revealed that over-expression of miR-215 inhibited cell proliferation and triggered cell cycle arrest at G2 phase, and that this effect was accompanied by a p53-dependent up-regulation of p21. The inhibitory effect on cell proliferation was more pronounced in cell lines containing wild-type p53, but was not seen in cells transfected with siRNAs against DHFR or TS. Moreover, denticleless protein homolog (DTL), a cell cycle-regulated nuclear and centrosome protein, was confirmed to be one of the critical targets of miR-215, and knock-down of DTL by siRNA resulted in enhanced G2-arrest, p53 and p21 induction, and reduced cell proliferation. Additionally, cells subjected to siRNA against DTL exhibited increased chemoresistance to MTX and TDX. Endogenous miR-215 was elevated about 3-fold in CD133+HI/CD44+HI colon cancer stem cells that exhibit slow proliferating rate and chemoresistance compared to control bulk CD133+/CD44+ colon cancer cells.Taken together, our results indicate that miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX. The findings of this study suggest that miR-215 may play a significant role in the mechanism of tumor chemoresistance and it may have a unique potential as a novel biomarker candidate.

Dataset Information

LncRNA Sox2OT-V7 promotes doxorubicin-induced autophagy and chemoresistance in osteosarcoma via tumor-suppressive miR-142/miR-22.

Publications

LncRNA Sox2OT-V7 promotes doxorubicin-induced autophagy and chemoresistance in osteosarcoma via tumor-suppressive miR-142/miR-22.

Similar Datasets

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