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Thrombomodulin regulates doxorubicin sensitivity through epithelial-mesenchymal transition in non-small cell lung
1Department of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. shun_lu@hotmail.com.
Objective:
Lung cancer has remained the highest about cancer-related mortality and drug resistance is involved in the recurrence of the disease. Thrombomodulin (TM) is down-regulated in several malignant tumors, but its role in drug resistance has not been elucidated in lung cancer. We aimed to investigate the role of TM in drug resistance to lung cancer.
Materials And Methods:
The mRNA and protein expression of TM were determined by real-time PCR and Western blot, respectively. TM expression was manipulated using siRNA or an overexpression system. The expression of epithelial-mesenchymal transition (EMT)-related markers (E-cadherin and vimentin) was detected by real-time PCR and Western blot.
Results:
We found that A549 and HCC827 cells with higher TM expression were more sensitive to doxorubicin than SPC-A-1 cells with lower TM. Also, downregulation of TM reduced the doxorubicin sensitivity in A549 and HCC827 cells. On the contrary, up-regulated TM increased the doxorubicin cytotoxicity in SPC-A-1 cells. Mechanically, ectopic expression of TM elevated the expression of E-cadherin, an epithelial marker. Conversely, overexpression of TM led to reduced expression of vimentin, a mesenchymal marker, leading to the reversal of EMT in lung cancer cells. As a result, SPC-A-1 cells overexpressing TM become more sensitive to doxorubicin treatment.
Conclusions:
These findings showed that TM regulated drug sensitivity through EMT in lung cancer cells, suggesting that TM might be developed into a novel target for lung cancer patients resistant to conventional therapeutics.
Insights
Thrombomodulin (TM) regulates drug sensitivity in lung cancer by reversing epithelial-mesenchymal transition (EMT). Upregulating TM can enhance chemotherapy effectiveness, offering a new therapeutic target for drug-resistant lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Lung cancer is a leading cause of cancer mortality.
- Drug resistance contributes significantly to lung cancer recurrence.
- The role of Thrombomodulin (TM) in lung cancer drug resistance is not well understood.
Purpose of the Study:
- To investigate the role of Thrombomodulin (TM) in the context of drug resistance in lung cancer.
- To explore the relationship between TM expression and sensitivity to chemotherapy agents.
- To elucidate the underlying mechanisms, including epithelial-mesenchymal transition (EMT), by which TM influences drug resistance.
Main Methods:
- Real-time PCR and Western blot were used to quantify TM mRNA and protein expression.
- TM expression levels were modulated using siRNA (knockdown) and overexpression systems.
- The expression of EMT markers, E-cadherin and vimentin, was assessed via real-time PCR and Western blot.
Main Results:
- Higher TM expression correlated with increased sensitivity to doxorubicin in lung cancer cell lines (A549, HCC827).
- Downregulation of TM decreased doxorubicin sensitivity, while upregulation enhanced it in resistant cells (SPC-A-1).
- TM overexpression promoted E-cadherin expression and reduced vimentin expression, indicating EMT reversal and increased doxorubicin sensitivity.
Conclusions:
- Thrombomodulin (TM) plays a crucial role in regulating drug sensitivity in lung cancer, potentially through the modulation of EMT.
- TM's ability to reverse EMT suggests it could be a novel therapeutic target for overcoming drug resistance in lung cancer patients.
- Targeting TM may offer a new strategy to improve treatment outcomes for individuals with refractory lung cancer.
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