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Lectin galactoside-binding soluble 3 binding protein mediates methotrexate resistance in choriocarcinoma cell lines
XiaoJing Chen1, Yite Xue1, Lingfang Wang1
1Key Laboratory of Women's Reproductive Health of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Abstract:
Choriocarcinoma is one of the most aggressive gestational trophoblastic neoplasias (GTN). Methotrexate (MTX) resistance is the main cause of treatment failure in choriocarcinoma. However, the mechanism of MTX resistance in choriocarcinoma is poorly known. This study aims to explore the function of Lectin galactoside-binding soluble 3 binding protein (LGALS3BP) in MTX-resistance in choriocarcinoma cells. Gradual dose escalation of MTX was used to establish MTX-resistant choriocarcinoma cells (JAR-MTX and JEG3-MTX cell lines). RNA-sequencing was used to explore the differentially expressed genes. Plasmids or SiRNA transfection was used to regulate the expression of LGALS3BP. ELISA was used to detect the concentrations of LGALS3BP in the serum of MTX-sensitive and MTX-resistant patients. qRT-PCR, Western blot, and CCK-8 assay were used to determine the effects of LGALS3BP on MTX-resistance in JAR and JEG3 cells. The results showed the relative resistance index (RI) of MTX is 791.50 and 1040.04 in JAR-MTX and JEG3-MTX, respectively. LGALS3BP was up-regulated in MTX-resistant cells compared to original cells in both RNA and protein level. The concentrations of LGALS3BP were higher in the sera of MTX-resistant patients than in MTX-sensitive patients. Knocking down LGALS3BP can reverse the MTX-resistance in JAR-MTX and JEG3-MTX cells. In summary, we preliminarily established two MTX-resistant cells, and performed RNA-sequencing, and found LGALS3BP may play important role in MTX-resistance. Our work not only provides a research tool (MTX-resistant cells) for other researchers, but gives some hint on how MTX resistance is regulated.
Insights
Lectin galactoside-binding soluble 3 binding protein (LGALS3BP) is upregulated in methotrexate-resistant choriocarcinoma, driving treatment failure. Reducing LGALS3BP levels can restore sensitivity to methotrexate, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Choriocarcinoma, an aggressive gestational trophoblastic neoplasia, often fails treatment due to methotrexate (MTX) resistance.
- The precise mechanisms underlying MTX resistance in choriocarcinoma remain largely unelucidated.
- Identifying novel targets is crucial for overcoming therapeutic limitations.
Purpose of the Study:
- To investigate the role of Lectin galactoside-binding soluble 3 binding protein (LGALS3BP) in mediating MTX resistance in choriocarcinoma cells.
- To establish and characterize MTX-resistant choriocarcinoma cell lines for mechanistic studies.
- To explore LGALS3BP as a potential biomarker and therapeutic target for MTX-resistant choriocarcinoma.
Main Methods:
- Established MTX-resistant choriocarcinoma cell lines (JAR-MTX, JEG3-MTX) via gradual dose escalation.
- Utilized RNA-sequencing to identify differentially expressed genes in resistant cells.
- Employed siRNA/plasmid transfection to modulate LGALS3BP expression and ELISA for serum analysis.
- Assessed MTX sensitivity using qRT-PCR, Western blot, and CCK-8 assays.
Main Results:
- Established MTX-resistant cell lines with high resistance indices (791.50 and 1040.04).
- LGALS3BP was significantly upregulated at both RNA and protein levels in MTX-resistant cells.
- Elevated LGALS3BP serum concentrations were observed in MTX-resistant patients compared to sensitive ones.
- Knockdown of LGALS3BP reversed MTX resistance in resistant choriocarcinoma cells.
Conclusions:
- LGALS3BP is significantly upregulated in MTX-resistant choriocarcinoma cells and patient sera.
- LGALS3BP plays a critical role in conferring MTX resistance in choriocarcinoma.
- LGALS3BP represents a potential therapeutic target for overcoming MTX resistance in gestational trophoblastic neoplasia.
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