Related Experiment Video
Updated: May 3, 2026
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by
Yong Zhou, Zufa Huang1, Song Wu
1Department of Orthopaedics, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China. zcy1958@medmail.com.cn.
Background:
miRNAs are involved in osteosarcoma (OS) chemoresistance, and TWIST reportedly enhances cisplatin-induced OS cell apoptosis by inhibiting multiple signaling pathways. In this study, we profiled miRNAs differentially expressed in chemoresistant OS, with a focus to identify miRNAs that regulate TWIST expression and OS chemoresistance.
Methods:
OS patients who showed <90% tumor necrosis after neochemotherapy were defined as poor responders (chemoresistant), and those who showed ≥90% tumor necrosis were defined as good responders (control). miRNA microarray analysis was carried out with a discovery cohort (n = 12) of age-, sex- and tumor stage-matched chemoresistant and control OS patients.
Results:
Among the up-regulated miRNAs in chemoresistant OS samples, miR-33a was verified to down-regulate TWIST expression, which was supported by an inverse miRNA-33a/TWIST expression trend in the validation cohort (n = 70), target-sequence-specific inhibition of TWIST-3' untranslated region-luciferase reporter activity by miR-33a, and alteration of TWIST expression by overexpression or inhibition of miR-33a in human OS cell lines. In Saos-2 cells treated with cisplatin, inhibition of miR-33a by antagomir-33a markedly increased cell apoptosis, which was enhanced by overexpression of TWIST. The apoptosis-inducing effect of TWIST overexpression was reversed by overexpression of miR-33a. In MG-63 cells, overexpression of miR-33a significantly decreased cisplatin-induced cell apoptosis, which was enhanced by knockdown of TWIST. Antagomir-33a significantly increased cisplatin-induced cell apoptosis, which was reversed by knockdown of TWIST.
Conclusions:
We have demonstrated in this study that miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level in OS. Our in vitro data indicate that miR-33a promotes OS cell resistance to cisplatin by down-regulating TWIST; on the other hand, inhibition of miR-33a by antagomir-33a enhances cisplatin-induced apoptosis in OS cells by up-regulating TWIST expression. The findings suggest that inhibition of miR-33a/TWIST signaling could be a potential new strategy to enhance neoadjuvant chemotherapy for OS.
Insights
MicroRNA-33a (miR-33a) is upregulated in chemoresistant osteosarcoma (OS), promoting cisplatin resistance by downregulating TWIST. Inhibiting miR-33a enhances apoptosis, suggesting a new therapeutic strategy for OS.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- MicroRNAs (miRNAs) play a role in osteosarcoma (OS) chemoresistance.
- TWIST protein is known to enhance cisplatin-induced OS cell apoptosis.
- This study aimed to identify miRNAs regulating TWIST expression and OS chemoresistance.
Purpose of the Study:
- To profile miRNAs differentially expressed in chemoresistant OS.
- To identify specific miRNAs that regulate TWIST expression.
- To investigate the role of identified miRNAs in OS chemoresistance.
Main Methods:
- miRNA microarray analysis was performed on chemoresistant and control OS patient samples.
- Expression levels of miR-33a and TWIST were analyzed in patient cohorts.
- In vitro studies utilized human OS cell lines (Saos-2, MG-63) with manipulations of miR-33a and TWIST.
Main Results:
- miR-33a was found to be upregulated in chemoresistant OS samples.
- miR-33a directly downregulates TWIST expression.
- Inhibition of miR-33a enhanced cisplatin-induced apoptosis by upregulating TWIST.
Conclusions:
- miR-33a is upregulated in chemoresistant OS and negatively correlates with TWIST protein levels.
- miR-33a promotes OS chemoresistance by downregulating TWIST.
- Inhibiting miR-33a may be a potential strategy to enhance neoadjuvant chemotherapy for OS.
Related Concept Videos
01:22MicroRNAs
01:22MicroRNAs
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
02:56Treatment Resistant Cancers
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...