A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell carcinoma metastasis, cancer stemness and drug resistance via enhancing β5-integrin/c-met signaling pathway

Abstract Background Naa10p (N-α-Acetyltransferase 10 protein) was reported to be involved in tumor invasion and metastasis in several of tumors. However, the role and mechanism of Naa10p mediated invasion and metastasis in oral squamous cell carcinoma (OSCC) remains undetermined. Methods The functional role of Naa10p in OSCC cells were determined using Transwell assay in vitro and xenograft tumorigenesis in nude mice. Immunoprecipitation, GST-pull down assays and immunofluorescence were performed to confirm the interaction between Naa10p and RelA/p65 in OSCC cells. Lastly, luciferase reporter assays, chromatin immunoprecipitation (ChIP) and western blot were used to evalute the effect of Naa10p expression on the Pirh2-p53 signaling pathway. Results Naa10p inhibits cell migration and invasion in vitro and attenuates the xenograft tumorigenesis in nude mice. Mechanistically, there is a physical interaction between Naa10p and RelA/p65 in OSCC cells, thereby preventing RelA/p65-mediated transcriptional activation of Pirh2. Consequently, inhibition of Pirh2 increased p53 level and suppressed the expression of p53 downstream targets, MMP-2 and MMP-9. Conclusion Naa10p function as a tumor metastasis suppressor in the progression of OSCC by targeting Pirh2-p53 axis, and might be a prognostic marker as well as a therapeutic target for OSCC.

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Cisplatin-Resistance in Oral Squamous Cell Carcinoma: Regulation by Tumor Cell-Derived Extracellular Vesicles

Cancers ◽

10.3390/cancers11081166 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1166 ◽

Cited By ~ 8

Author(s):

Xin-Hui Khoo ◽

Ian C. Paterson ◽

Bey-Hing Goh ◽

Wai-Leng Lee

Keyword(s):

Drug Resistance ◽

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Extracellular Vesicles ◽

Squamous Cell ◽

Metal Ion ◽

De Novo ◽

Protein Profile ◽

Severe Problem

Drug resistance remains a severe problem in most chemotherapy regimes. Recently, it has been suggested that cancer cell-derived extracellular vesicles (EVs) could mediate drug resistance. In this study, the role of EVs in mediating the response of oral squamous cell carcinoma (OSCC) cells to cisplatin was investigated. We isolated and characterized EVs from OSCC cell lines showing differential sensitivities to cisplatin. Increased EV production was observed in both de novo (H314) and adaptive (H103/cisD2) resistant lines compared to sensitive H103 cells. The protein profiles of these EVs were then analyzed. Differences in the proteome of EVs secreted by H103 and H103/cisD2 indicated that adaptation to cisplatin treatment caused significant changes in the secreted nanovesicles. Intriguingly, both resistant H103/cisD2 and H314 cells shared a highly similar EV protein profile including downregulation of the metal ion transporter, ATP1B3, in the EVs implicating altered drug delivery. ICP-MS analysis revealed that less cisplatin accumulated in the resistant cells, but higher levels were detected in their EVs. Therefore, we inhibited EV secretion from the cells using a proton pump inhibitor and observed an increased drug sensitivity in cisplatin-resistant H314 cells. This finding suggests that control of EV secretion could be a potential strategy to enhance the efficacy of cancer treatment.

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