Abstract
RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyper-recombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers.
Highlights
Two-thirds of head and neck squamous cell carcinoma (HNSCC) cases have locally advanced lesions with or without regional lymph node involvement [1]
RECQL1 and WRN proteins are abundantly expressed in hypopharyngeal carcinoma
Both proteins were strongly stained in hypopharyngeal cancer cells compared with stromal fibroblasts, they were less stained in breast cancer cells (Fig. 1C)
Summary
Two-thirds of head and neck squamous cell carcinoma (HNSCC) cases have locally advanced lesions with or without regional lymph node involvement [1]. Despite recent advances in therapeutic procedures, the 5-year survival rate for patients with HNSCC has remained 50% or less for the past few decades [2]. Hypopharyngeal carcinoma has one of the worst prognoses among HNSCCs, and the 5-year survival rate is approximately 30% to 35% [3]. Hypopharyngeal carcinoma is prominently invasive, and total pharyngolaryngectomy, which is the curative surgical treatment, causes serious functional problems that include vocal, swallowing, and chewing disorders [4]. Hypopharyngeal carcinoma often metastasizes to lymph nodes or distant organs, and innovations to improve disease survival and larynx preservation are needed.
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