Mice were treated intravenously with in vivo-jetPEI-formulated mir-22 inhibitor for 4 weeks. Separate groups of animals bearing CAL27 xenograft tumors were treated with the same doses of in vivo-jetPEI-formulated tRNA/MSA as controls. Meanwhile, 2 mg/kg cisplatin or equal volumes saline was intraperitoneally injected every other day for 4 weeks.

BACKGROUND: Tongue squamous cell carcinoma (TSCC) is the most common oral cancer. Neoadjuvant systemic treatment before or after surgery for advanced TSCC is considered one of the most crucial factors in reducing mortality. However, the therapeutic benefits of chemotherapy are usually attenuated due to intrinsic and/or acquired drug resistance, and a large proportion of TSCC are resistant to chemotherapy, which may result in more aggressive tumor behavior and an even worse clinical outcome. Recently, the potential application of using miRNAs to predict therapeutic response to cancer treatment holds high promise, but miRNAs with predictive value remain to be identified and underlying mechanisms remain to be understood in TSCC. METHODS: The expression of miR-22 in tissues from patients diagnosed with TSCC was analyzed using real-time PCR. The effects of miR-22 on cell proliferation and tumorigenesis in TSCC cells were analyzed by MTS assay, and flow cytometry. The tumor growth in vivo was observed in xenograft model. Luciferase reporter assay, real-time PCR and western blot were performed to validate a potential target of miR-22 in TC. The correlation between miR-22 expression and KAT6B expression, as well as the mechanisms by which miR-22 regulates PI3k-Akt-NF-kB pathway in TSCC were also addressed. RESULTS: We found a strong correlation between miR-22 expression and chemosensitivity to cisplatin (CDDP) in TSCC patients. Ectopic overexpression of miR-22 enhanced TSCC cells apoptosis in response to CDDP in experimental models performed in vitro and in vivo. Moreover, we found that KAT6B is a direct functional target of miR-22. Ectopic expression of KAT6B attenuated the efficiency of miR-22 in TSCC cells upon CDDP treatment. Mechanistically, miR-22 overexpression or KAT6B knockdown inhibited PI3K/Akt/NF-kappaB signaling in TSCC cells, possibly via downregulating the activators of PI3K/Akt/NF-kappaB signaling, such as S100A8, PDGF and VEGF. Furthermore, the activation of miR-22 depended on the intensity of the stresses in the presence of p53 activation. CONCLUSIONS: Our findings define miR-22 as an intrinsic molecular switch that determines p53-dependent cellular fate through KAT6B/ PI3K-Akt/ NF-kB pathway.