Oral and maxillofacial malignancy is one of the most lethal tumors and a major leading cause of mortality due to local recurrence or metastasis, however, there is lack of epidemiological data on its exact prevalence. An estimated 300,400 new cases and 145,400 deaths from oral cavity cancer (including lip cancer) occurred in 2012 worldwide , and in China an estimated annual incidence of 1.6–1.9 per 100,000 persons was assessed . The usual age at diagnosis of oral cancer is between 55 and 65 years old and males are affected twice as often as females and SCC is most likely to appear in males over 40 years of age with a history of heavy alcohol use coupled with smoking .
In our study about SCC in OMF, males are more involved than females with a ratio of 1.44:1, with a peak age of 45–74 years. Oral cavity is the most commonly affected primary region accounting for 79.51% of all the cases, followed by lip and oral pharynx.
Zinc is an essential trace element which can act as a co-factor for more than 300 enzymes that regulate a variety of cellular processes and signaling pathways . The imbalance of Zinc homeostasis has been established in varied pathological conditions, including many types of cancer, such as prostate cancer, breast cancer, lung cancer and ovarian cancer .
There are three main parameters commonly used to detect Zinc level of human body: tissue Zinc, serum Zinc and excrement Zinc. Tissue Zinc is more specific and sensitive to indicate the alternation of Zinc level, however, it needs a high quality of experimental condition and is relatively complicated to operate. The utility of excrement Zinc as a measure of Zinc status, such as urinary Zinc, is also limited by the difficulties encountered in collecting a 24 h specimen without exogenous Zinc contamination . Blood is easy to be harvested and many studies provide evidence that the trend of changes of Zinc level in tissue and serum is consistent, which makes serum Zinc to be an acceptable clinical index to demonstrate the alteration of Zinc status . In our study, serum Zinc was applied to indicate the Zinc status of human body.
Despite current advances in its fundamental research and clinical management, the OMF cancer remains a difficult region to control. Surgery is still the most important treatment method in SCC of OMF, cancer can be highly curable if detected early, while it is hard to excise completely due to the restriction of anatomy and tissue defects created by extensive resection can severely affect speech and swallowing function as well as destroy the aesthetic appearance at late stage. A 5-year survival remains poor at 62.7% in the USA and below 50% in other countries due to local recurrence and distant metastatic spread even the combination of chemotherapy and radiotherapy were applied in patients [10, 11]. Thus, further study into its pathogenesis and predictors of outcome is critical to devise a new preventive measure, clarify an earlier diagnosis, and offer a novel treatment modality to SCC of OMF.
In our study, the concentration of serum Zinc in SCC decreased significantly compared to the controls. Increased prevalence of sZnd in SCC group was observed and calculated to be statistically significant versus controls. Serum Zinc level reduced and incidence of sZnd increased were observed with the progression of tumor grade, the difference were statistically significant between early stage ( T1、T2 ) and late stage ( T3、T4 ) using Chi-square test. SCC of OMF has a propensity for cervical nodal spread. In our research we found that concentration of serum Zinc in SCCs accompanied lymph node metastasis decreased significantly to those without metastasis. SCC patients suffering from sZnd had a more higher risk of having metastasis compared with those with normal serum Zinc. The results above demonstrated that decreased serum Zinc level, especially sZnd, was a predisposing indicator to the tumorigenesis of SCC, and also a promoter to its aggravation and lymph node metastasis.
sZnd has been proved significantly associated to the development and aggravation of SCC of OMF in our study, however, the exact mechanism remains poorly uncovered. Up to date, the underlying mechanisms may include: ① Zinc serves as a co-factor in Zinc-dependent matrix metalloproteinases which augment autodebridement and keratinocyte migration during wound repair and its importance in wound healing is well appreciated [12, 13]. The most common clinical presentation of SCC of OMF is an incurable ulcer, such as tongue cancer, buccal cancer and mouth floor cancer , Zinc deficiency in tumor microenvironment may delay wound healing and lead to pathological changes of SCC. Zinc deficiency is commonly detected in patients with recurrent aphthous ulceration (RAU), and improvement in oral wound healing rates and reduction in the recurrence rate have been observed clinically in RAU via systematic Zinc supplementation [15, 16], thus Zinc administration could be a novel anticancer therapeutic candidate in SCC; ② Multiple lifestyle or environmental factors, such as tobacco use, alcohol abuse, chemical exposure and virus infection, can cause DNA damage and abnormalities of genome integrity. Zinc plays an important role in transcription factor function, antioxidant defense and DNA repair. Deficiencies in Zinc can contribute to single- and double-strand DNA breaks and oxidative modifications to DNA that increase risk for cancer development . Oncogenesis of SCC occurs as a result of the accumulation of gene and chromosome mutations . Benefits maybe gained from Zinc supplement through repairing DNA damage and maintaining integrity of chromosomes and genes in patients with SCC; ③ Zinc deficiency has been well documented in many cancers with elevated level of Hedgehog (Hh) ligand both in patient serum and affected tissues. When Zinc levels are low, Hh autoprocessing may be enhanced, leading to overproduction of Hh ligand and potentially abnormal activation of Hh signaling pathway . Hedgehog (Hh) signaling pathway stimulation has been observed in oral squamous cell carcinomas and this low Zinc-high Hh axis may contribute to its pathogenesis . Thus cancer prevention could be achieved by Zinc fuels that Zinc can bind to the active site of the Hedgehog-intein (Hint) domain and inhibit Hh ligand production; ④ It is well established that there exist comprehensive interactions between tumor immunology and tumor biology in head and neck squamous cell carcinoma . Zinc is required for the activity of many enzymes for proper immune function. Zinc deficiency affects multiple aspects of innate and adaptive immunity, including thymic atrophy, altered thymic hormones, lymphopenia, and compromised cellular-and antibody-mediated responses that reduces the lytic activity of natural killer cells, impairs NKT cell cytotoxicity and immune signaling . Zinc supplementation might either restore function in the setting of dysfunction or improve normal immune cell function in SCC which would be contributed to the development of customized treatment strategy.