Abstract
Drug resistance to platinum limited therapeutic options for oral squamous cell carcinoma (OSCC). In the current study, we investigated the role of lncRNA HOMEOBOX A11 (HOXA11) antisense RNA (HOXA11-AS) in OSCC resistance to cisplatin (CDDP). We used clinical tissues and OSCC cell lines and induced CDDP resistance in OSCC cells. Gain and loss of function were performed in OSCC-resistant cells. Xenograft mice were also established. HOXA11-AS expression was increased in OSCC clinical tissues and cell lines and upregulated in CDDP-resistant cells. Upregulation of HOXA11-AS promoted proliferation in CDDP-sensitive cells and inhibited CDDP-induced cytotoxicity. In contrast, downregulation of HOXA11-AS decreased proliferation in CDDP-resistant cells and increased CDDP-induced cytotoxicity. Knockdown of HOXA11-AS inhibited the tumor growth in xenograft mice injected by CDDP. Downregulation of HOXA11-AS increased apoptosis and caspase 3 activities in CDDP-resistant OSCC cells. Bioinformatics, reporter assay, and loss and gain of function assay indicated that HOXA11-AS and miR-214-3p could negatively regulate each other. miR-214-3p was decreased in OSCC clinical tissues and cell lines. We further revealed that proto-oncogene serine/threonine-protein kinase (PIM1) was the target of miR-214-3p. PIM1 expression could be negatively regulated by miR-214-3p and positively regulated by HOXA11-AS. Inhibition of PIM1 suppressed anti-miR-214-3p-induced increase of cell proliferation and decrease of apoptosis. In summary, HOXA11-AS was identified to facilitate CDDP-resistance in OSCC and miR-214-3p/PIM1 was found to be the downstream target of HOXA11-AS. The findings highlight the importance of HOXA11-AS/miR-214-3p/PIM1 axis in the drug resistance of OSCC and provide potential targets for improving chemotherapy of OSCC.
Highlights
Oral squamous cell carcinoma (OSCC) is one of the most common head and neck squamous cell carcinomas (HNSCCs) with a changing molecular and demographic profile [1,2,3,4]
The expression pattern of HOMA11-AS in OSCC tissues and cells was examined and the results showed that HOMA11-AS expression in OSCC clinical tissues was significantly higher than that in adjacent normal tissues (Figure 1(a))
The results suggested that HOMA11-AS upregulation was involved in CDDP-resistance in OSCC cells
Summary
Oral squamous cell carcinoma (OSCC) is one of the most common head and neck squamous cell carcinomas (HNSCCs) with a changing molecular and demographic profile [1,2,3,4]. OSCC occupies approximately 3% of all recently diagnosed clinical cancer cases [1]. Despite the substantial improvements in multimodality approaches, the cure rate in those patients receiving such treatments is only 50% [5]. The overall 5-year survival rate of OSCC patients is less than 50% [6]. Chemotherapy (such as platinum) is an efficient adjuvant treatment for OSCC patients in some cases. Drug resistance to platinum limited therapeutic options with a median overall survival time of 6-9 months in OSCC [7]. Thereof, the better understanding of the molecular mechanisms underlying platinum-based drug resistance in OSCC is urgently needed for the efficient therapy of OSCC patients
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