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Published on: January 9, 2020
Adenovirus expressing IFN-λ (Ad/hIFN-λ) produced anti-tumor effects through inducing apoptosis in human tongue
Bing Song1, Yong Yang1, Yan-Li Wang2
1Department of Oral and Maxillofacial Surgery, Binzhou Medical University Hospital Binzhou 256603, China.
Objective:
To investigate the potential therapeutic effects of adenovirus expressing IFN-λ1 and IFN-λ2 (Ad/hIFN-λ) in treating squamous cell carcinoma of the oral tongue (SCCOT) and to explore the underlying mechanisms.
Methods:
Two SCCOT cell lines HSC-3 and Tca8113 were adopted as study objects. Cell Counting Kit-8 (CCK-8) cell proliferation and viability assay was performed to evaluate the antiproliferative effects of Ad/hIFN-λ and IFN-λ treatments at different dosages. Flow cytometry (FCM) was performed to investigate the apoptosis rate induced by Ad/hIFN-λ. In vivo study was performed through evaluating tumorigenicity and tumor volume on BALB/c nu/nu mice inoculated with HSC-3 cells with or without infection of Ad/hIFN-λ. qPCR was used to screen important apoptosis related genes expression and western blot (WB) was performed to verify the results. WB was also used to test the phosphorylation of STATs protein in the JAK/STAT signaling pathways.
Results:
Our results indicated an obvious antiproliferative effect of Ad/hIFN-λ in vitro on infected HSC-3 and Tca8113 cells. The antiproliferative effects started to appear at 48 h (day 2) after infection. IFN-λs alone treating HSC-3 and Tca8113 cells also showed a dose-dependent inhibitory manner. Though the antiproliferative effects did not show on 24 h (day 1), early apoptosis rate already increased significantly in cells infected with Ad/hIFN-λ (P<0.05) detected by FCM. The underlying mechanisms of antiproliferative activity rely on the IFN-λ signaling by phosphorylation of STATs protein. Expression of Bax, Bcl-2 and Caspase-3 were promoted by Ad/hIFN-λ leading to higher apoptosis rate. Upper stream of p21 and Rb dephosphorylation explained the Caspase-3 activation. Animal study showed that HSC-3 cells infected with Ad/hIFN-λ significantly promoted the survival rate and decreased mean tumor volume comparing to HSC-3 cells group.
Conclusion:
Ad/hIFN-λ injection had obvious antiproliferative effects on HSC-3 and Tca8113 cells. Ad/hIFN-λ induced apoptosis in SCCOT cells through increasing Bcl-2, Bax and Caspase-3 expression. Ad/hIFN-λ is a potential therapeutic strategy in treating oral tongue carcinoma.
Insights
Adenovirus expressing interferon-lambda (Ad/hIFN-λ) demonstrated significant antiproliferative effects against oral tongue squamous cell carcinoma cells. This therapy induces apoptosis and holds potential for treating oral tongue carcinoma.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Molecular oncology
Background:
- Squamous cell carcinoma of the oral tongue (SCCOT) presents a significant therapeutic challenge.
- Interferon-lambda (IFN-λ) has shown promise in cancer treatment.
- Adenoviral vectors offer a platform for targeted gene delivery.
Purpose of the Study:
- To evaluate the therapeutic efficacy of adenovirus expressing IFN-λ1 and IFN-λ2 (Ad/hIFN-λ) against SCCOT.
- To elucidate the molecular mechanisms underlying Ad/hIFN-λ's anti-cancer effects.
- To assess the in vivo anti-tumor activity of Ad/hIFN-λ.
Main Methods:
- In vitro studies utilized SCCOT cell lines (HSC-3, Tca8113) to assess proliferation and apoptosis via CCK-8 assays and flow cytometry.
- In vivo efficacy was evaluated in BALB/c nu/nu mice bearing HSC-3 tumors.
- Gene expression (qPCR) and protein analysis (Western Blot) investigated apoptosis-related genes and JAK/STAT signaling pathway activation.
Main Results:
- Ad/hIFN-λ exhibited significant dose-dependent antiproliferative effects on SCCOT cells in vitro, with effects apparent by 48 hours post-infection.
- Increased early apoptosis was observed in Ad/hIFN-λ infected cells, mediated by the JAK/STAT pathway and altered expression of Bax, Bcl-2, and Caspase-3.
- In vivo studies demonstrated that Ad/hIFN-λ treatment significantly improved survival rates and reduced tumor volume in mice.
Conclusions:
- Ad/hIFN-λ demonstrates potent anti-SCCOT activity through induction of apoptosis.
- The mechanism involves modulation of key apoptotic proteins and JAK/STAT signaling.
- Ad/hIFN-λ represents a promising therapeutic candidate for oral tongue carcinoma.
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