Oral Oncology 50 (2014) e55–e56

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Oral Oncology

journal homepage: www.elsevier .com/locate /ora loncology

Letter to the Editor

Role of Statherin in oral carcinogenesis

http://dx.doi.org/10.1016/j.oraloncology.2014.07.0121368-8375/� 2014 Elsevier Ltd. All rights reserved.

Statherin is a protein in humans encoded by the STATH gene. Itprevents calcium phosphate precipitation in saliva, thusmaintaining a high calcium and phosphate levels [1]. The activeregion for inhibition of calcium phosphate precipitation residesin the highly charged amino-terminal and the neutral tyrosine-,glutamine- and proline-rich carboxy-terminal of the molecule[2]. By virtue of this, statherin plays a very important role in main-taining the mineralization of enamel surface [3] and promotingantimicrobial function [4].

There is significant reduction in statherin levels in saliva ofprecancerous and cancerous lesions of oral cavity. In contrast,non-alteration of statherin levels in inflammatory or salivary glandtumors indicates its exclusive relation with oral cancer and pre-cancer [5]. However, the mechanism of action of statherin in oralcarcinogenesis is still remained unanswered.

Calcium is an important regulator of epithelial differentiationin vitro. Low concentration calcium causes sustained proliferationand lack of desmosomes. In contrast, at higher calcium levels theyexpress differentiation markers and displays better stratification(through desmosomes) [6]. Moreover, calcium induces a G1 cell-cycle arrest that results in part from increased p21WAFI andp27KIPI expression and subsequent inhibition of cyclin-dependentkinases [7]. Some calcium binding proteins are cross-linked at ornear plasma membrane into cornified envelope. The effects ofcalcium are mediated by the protein kinase C pathway, whichinduces late-differentiation markers (loricrin, profilaggrin) andcornified envelope formation [8].

In the oral cavity, epithelium is continuously bathe in salivaand its composition. We believe that free calcium levels in saliva,maintained by statherin, is important for maintaining the integ-rity of epithelium by inducing proper differentiation. It is wellknown that an elevation of cytoplasmic calcium can result fromcalcium-influx from the extracellular space through a variety ofplasma membrane ion channels. More specifically, voltage- andligand-gated calcium channels in the plasma membrane, alongwith intracellular ryanodine receptors and inositol (1,4,5)-tri-phosphate (InsP3) receptors in the endoplasmic reticulum aswell as mitochondrial voltage-dependent anion channels andcalcium ion exchangers provide fluxes of calcium to thecytoplasm [9].

As a ubiquitous intracellular signaling molecule, calcium isinvolved in the regulation of almost all cellular functions includinggene transcription, metabolism, proliferation and apoptosis [9,10].Many carcinogenesis related processes such as increased prolifer-ation, decreased differentiation and decreased apoptosis are asso-ciated with intracellular calcium concentrations.

Thus, presence of statherin and its inhibitory aspect of calciumphosphate precipitation creates unique microenvironment in theoral cavity to which oral epithelium is constantly subjected. Weproposed that decreased levels of statherin in saliva result in lowconcentration of free calcium in the oral cavity. Consequently,decreased influx of calcium leads to less availability of intra-cellu-lar calcium causing initiation of carcinogenesis related aforemen-tioned processes. We also believe that such lack of calciumcauses less expression of desmosomes junctions (cell adhesion)and cornified envelope enabling an increased penetration of envi-ronmental carcinogens through the mucosal surface.

We recommend future studies on in vivo salivary calcium influxin the oral epithelia and its role in cellular differentiation and pro-liferation. Moreover, effects of statherin on intracellular calciumlevel and its subsequent related molecular alterations would giveus new pathogenic aspect in oral carcinogenesis.

Conflict of Interest

None declared.

Funding source

None.

References

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[8] Dlugosz AA, Yuspa SH. Coordinate changes in gene expression which mark thespinous to granular cell transition in epidermis are regulated by protein kinaseC. J Cell Biol 1993;120:217–25.

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e56 Letter to the Editor / Oral Oncology 50 (2014) e55–e56

Sachin C. SarodeGargi S. Sarode 1

Snehal PatilDepartment of Oral Pathology and Microbiology, Dr. D.Y. Patil DentalCollege and Hospital, Dr. D.Y. Patil Vidyapeeth, Maheshnagar, Pimpri,

Pune – 18, Maharashtra, IndiaTel.: +91 9922491465.

E-mail addresses: drsachinsarode@gmail.com (S.C. Sarode),gargi14@gmail.com (G.S. Sarode).

Available online 13 August 2014

1 Tel.: +91 9823871462.