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Published on: January 19, 2019
Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor
Wen Lei1, Hong-bin Liu, Shi-bing Wang
1Xinyuan Institute of Medicine and Biotechnology, College of Biological Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.
Aim:
The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer, and frequently inactivated in primary non-small cell lung cancer (NSCLC). In this study, we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer, and the mechanisms underlying the antitumor actions.
Methods:
The recombinant virus Ad·sp-E1A(Δ24)-TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·sp-E1A(Δ24) vector, which contained the survivin promoter and a 24 bp deletion within E1A. The antitumor effects of Ad·sp-E1A(Δ24)-TSLC1 were evaluated in NCI-H460, A549, and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5, as well as in A549 xenograft model in nude mice. Cell viability was assessed using MTT assay. The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses. The tumor tissues from the xenograft models were examined using H&E staining, IHC, TUNEL, and TEM analyses.
Results:
Infection of A549 lung cancer cells with Ad·sp-E1A(Δ24)-TSLC1 induced high level expression of TSLC1. Furthermore, the Ad·sp-E1A(Δ24)-TSLC1 virus dose-dependently suppressed the viability of NCI-H460, A549, and H1299 lung cancer cells, and did not affect MRC-5 normal fibroblast cells. Infection of NCI-H460, A549, and H1299 lung cancer cells with Ad·sp-E1A(Δ24)-TSLC1 induced apoptosis, and increased activation of caspase-8, caspase-3 and PARP. In A549 xenograft model in nude mice, intratumoral injection of Ad·sp-E1A(Δ24)-TSLC1 significantly suppressed the tumor volume, and increased the survival rate (from less than 15% to 87.5% at d 60). Histological studies showed that injection of Ad·sp-E1A(Δ24)-TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues.
Conclusion:
The oncolytic adenovirus Ad·sp-E1A(Δ24)-TSLC1 exhibits specific antitumor effects, and is a promising agent for the treatment of lung cancer.
Insights
This study shows that the oncolytic adenovirus Ad·sp-E1A(Δ24)-TSLC1 effectively targets and suppresses non-small cell lung cancer (NSCLC) cell viability and tumor growth. The engineered virus demonstrates significant antitumor activity and increased survival rates in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Molecular oncology
- Gene therapy for cancer
Background:
- Tumor suppressor in lung cancer-1 (TSLC1) is frequently inactivated in non-small cell lung cancer (NSCLC).
- Oncolytic adenoviruses offer a targeted approach for cancer treatment.
Purpose of the Study:
- To investigate the antitumor effects of a dual-regulated oncolytic adenovirus (Ad·sp-E1A(Δ24)-TSLC1) expressing TSLC1 in lung cancer.
- To elucidate the underlying mechanisms of its antitumor actions.
Main Methods:
- Construction of the recombinant Ad·sp-E1A(Δ24)-TSLC1 virus.
- Evaluation of antitumor effects in NSCLC cell lines (NCI-H460, A549, H1299) and a xenograft model.
- Assessment of cell viability, apoptosis, caspase activation, and viral propagation in tumor tissues.
Main Results:
- Ad·sp-E1A(Δ24)-TSLC1 induced high TSLC1 expression and selectively suppressed lung cancer cell viability.
- The virus triggered apoptosis via caspase-8, caspase-3, and PARP activation in cancer cells.
- Significant tumor volume reduction and increased survival rates were observed in xenograft models, with evidence of apoptosis and viral propagation.
Conclusions:
- The oncolytic adenovirus Ad·sp-E1A(Δ24)-TSLC1 demonstrates specific antitumor efficacy against lung cancer.
- This engineered virus represents a promising therapeutic agent for lung cancer treatment.
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