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A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing
Szu-Jen Wang1, Pei-Ming Yang2,3,4,5
1Division of Gastroenterology, Department of Internal Medicine, Yuan's General Hospital, Kaohsiung 80249, Taiwan.
Abstract:
Hepatocellular carcinoma (HCC) is a relatively chemo-resistant tumor. Several multi-kinase inhibitors have been approved for treating advanced HCC. However, most HCC patients are highly refractory to these drugs. Therefore, the development of more effective therapies for advanced HCC patients is urgently needed. Stathmin 1 (STMN1) is an oncoprotein that destabilizes microtubules and promotes cancer cell migration and invasion. In this study, cancer genomics data mining identified STMN1 as a prognosis biomarker and a therapeutic target for HCC. Co-expressed gene analysis indicated that STMN1 expression was positively associated with cell-cycle-related gene expression. Chemical sensitivity profiling of HCC cell lines suggested that High-STMN1-expressing HCC cells were the most sensitive to MST-312 (a telomerase inhibitor). Drug-gene connectivity mapping supported that MST-312 reversed the STMN1-co-expressed gene signature (especially BUB1B, MCM2/5/6, and TTK genes). In vitro experiments validated that MST-312 inhibited HCC cell viability and related protein expression (STMN1, BUB1B, and MCM5). In addition, overexpression of STMN1 enhanced the anticancer activity of MST-312 in HCC cells. Therefore, MST-312 can be used for treating STMN1-high expression HCC.
Insights
Hepatocellular carcinoma (HCC) is resistant to chemotherapy. High Stathmin 1 (STMN1) expression predicts poor prognosis, but MST-312 shows promise in treating STMN1-high HCC.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Hepatocellular carcinoma (HCC) exhibits chemoresistance, necessitating novel therapeutic strategies.
- Stathmin 1 (STMN1), an oncoprotein, is implicated in cancer progression and serves as a potential therapeutic target in HCC.
- Existing multi-kinase inhibitors show limited efficacy in advanced HCC patients.
Purpose of the Study:
- To identify prognostic biomarkers and therapeutic targets for advanced Hepatocellular carcinoma (HCC).
- To investigate the therapeutic potential of MST-312, a telomerase inhibitor, in HCC, particularly in relation to STMN1 expression.
Main Methods:
- Cancer genomics data mining to identify STMN1 as a prognostic biomarker and therapeutic target.
- Co-expressed gene analysis to understand STMN1's molecular interactions.
- Chemical sensitivity profiling of HCC cell lines with varying STMN1 expression.
- Drug-gene connectivity mapping to assess MST-312's effect on STMN1-associated gene signatures.
- In vitro experiments to validate MST-312's efficacy and mechanism of action.
Main Results:
- STMN1 was identified as a prognostic biomarker and therapeutic target in HCC.
- High STMN1 expression correlated with sensitivity to MST-312, a telomerase inhibitor.
- MST-312 treatment inhibited HCC cell viability and key protein expression (STMN1, BUB1B, MCM5).
- Overexpression of STMN1 potentiated the anticancer effects of MST-312 in HCC cells.
Conclusions:
- MST-312 demonstrates therapeutic potential for Hepatocellular carcinoma (HCC) patients with high STMN1 expression.
- Targeting STMN1 in combination with MST-312 may offer a novel treatment strategy for advanced HCC.
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