Abstract
Solute carrier family 22 member 3 (SLC22A3), also called organic cation transporter 3 (OCT3), is responsible for organic cation transport, which can eliminate many endogenous small organic cations, drugs, and toxins. This study investigated whether SLC22A3 expression is related to cisplatin uptake and the survival of patients with head and neck squamous cell carcinoma (HNSCC). Using immunohistochemical staining and digital image analysis, SLC22A3 expression was examined in 42 HNSCC patients who were postoperatively treated with or without adjuvant chemotherapy. SLC22A3-overexpressing SCC-4 cells and SLC22A3-knocked down SCC-25 cells were used to investigate the function of SLC22A3 in cisplatin uptake. We found that patients with higher SLC22A3 expression had longer survival times than those with lower SLC22A3 expression (p = 0.051). Moreover, among advanced T-stage patients receiving adjuvant cisplatin therapy, those with higher SLC22A3 expression had longer survival times than those with lower SLC22A3 expression (p = 0.006). An in vitro study demonstrated that SCC-25 cells with upregulated SLC22A3 expression were more sensitive to cisplatin than were SCC-4 cells with downregulated SLC22A3 expression. An increased uptake of cisplatin and an enhanced cytotoxic effect were observed in SLC22A3-overexpressing SCC-4 cells, and decreased uptake was found in SLC22A3-knocked down SCC-25 cells. Our results demonstrated that upregulated SLC22A3 expression can increase the cisplatin uptake and subsequently improve the survival of patients with HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the tenth most common cancer in men worldwide and is currently the seventh most common cause of cancerrelated death [1]
This study investigated whether SLC22A3 expression is related to cisplatin uptake and the survival of patients with head and neck squamous cell carcinoma (HNSCC)
We found that among patients receiving cisplatin therapy, those with higher SLC22A3 expression had a higher 2-year survival rate than those with lower SLC22A3 expression (p = 0.036) (Figure 2B)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the tenth most common cancer in men worldwide and is currently the seventh most common cause of cancerrelated death [1]. The standard treatments for HNSCC consist of surgery, radiotherapy, chemotherapy and combinations of these modalities [2]. HNSCC may be curable with surgery, radiation, and chemotherapy. In the advanced stage, tumor recurrence and metastasis may occur after primary treatment and are associated with a poor outcome. Solute carrier family 22 member 3 (SLC22A3), called organic cation transporter 3 (OCT3), is an imprinted gene located on human chromosome 6. In mouse models of cisplatin ototoxicity, SLC transporters (e.g. CTR1 and OCT2) had been associated with cisplatin-induced ototoxicity. Organic cation/carnitine transporters rOctn and rOctn may mediate oxaliplatin induced neurotoxicity in rats [5]. SLC transporters expressed in the small intestine, liver, and kidney may play an important role in the disposition of cancer drugs [6] and expressed in cancer cells play an important role in the cellular uptake of anticancer drugs, which may be a determinant step of anticancer drug efficacy [6]
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