Abstract
Clinical investigations suggest that melatonin suppression and circadian dysfunction may be related to cancer development in shift workers. Studies also show that melatonin suppression after pinealectomy increases cancer incidence in preclinical models. However, no study evaluated the influence of pinealectomy on oral cancer development. In the current study, we investigated the effects of pinealectomy on oral squamous cell carcinoma (OSCC) occurrence and progression in rats. Rats submitted to sham surgery were used as control. Pinealectomy promoted an increase of 140% in OSCC occurrence when compared to sham animals. Tumors from pinealectomized rats displayed a higher volume and thickness than the tumors from sham-operated animals. Pinealectomy induced atrophy of the epithelium adjacent to the oral lesions. Pinealectomized rats showed higher mean number of tumor-associated macrophages and eosinophils in the invasive front of OSCC. In addition, nuclear overexpression of ERK1/2 and p53 was also observed in the front of carcinomas from pinealectomized rats. These results reveal that pineal gland plays a protective role against oral carcinogenesis. The melatonin suppression caused by the pinealectomy might contribute to oral cancer development by acting on ERK1/2 and p53 pathways and regulating tumor inflammation.
Highlights
Head and neck cancer (HNC) is the 6th most incident, while only oral cancer affects about 350.000 people worldwide [1]
All pinealectomized (PNT) and sham rats were submitted to chemically induced carcinogenesis to investigate the effect of melatonin suppression on oral cancer occurrence
The cancer animals were not treated with melatonin, the results of this study suggest that the pinealectomy may promote chemically induced oral squamous cell carcinoma (OSCC) growth in rats through nuclear overexpression of Extracellular signal-regulated kinases (ERK1/2) and dysfunctional p53
Summary
Head and neck cancer (HNC) is the 6th most incident, while only oral cancer affects about 350.000 people worldwide [1]. Studies have shown that melatonin, a major hormone of pineal gland, may be used as adjuvant therapy for cancer treatment [2,3,4]. Melatonin may affect tumor growth by reducing cell proliferation and angiogenesis and inhibiting DNA damage [8]. A study showed that lung metastasis of gastric cancer may be inhibited by melatonin through the downregulation of MMP-2, MMP-9, and NF-κB [9]. In Trp53−/− mice, melatonin administration inhibited lymphoma development [13]. Another recent study showed in an orthotopic model of oral cancer that melatonin administration reduced the p-ERK levels in the tumor microenvironment [14]
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