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Role of Statherin in oral carcinogenesis
Oral Oncology 50 (2014) e55–e56
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Letter to the Editor Role of Statherin in oral carcinogenesis
Statherin is a protein in humans encoded by the STATH gene. It prevents calcium phosphate precipitation in saliva, thus maintaining a high calcium and phosphate levels [1]. The active region for inhibition of calcium phosphate precipitation resides in 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 maintaining the mineralization of enamel surface [3] and promoting antimicrobial function [4]. There is significant reduction in statherin levels in saliva of precancerous and cancerous lesions of oral cavity. In contrast, non-alteration of statherin levels in inflammatory or salivary gland tumors indicates its exclusive relation with oral cancer and precancer [5]. However, the mechanism of action of statherin in oral carcinogenesis is still remained unanswered. Calcium is an important regulator of epithelial differentiation in vitro. Low concentration calcium causes sustained proliferation and lack of desmosomes. In contrast, at higher calcium levels they express differentiation markers and displays better stratification (through desmosomes) [6]. Moreover, calcium induces a G1 cellcycle arrest that results in part from increased p21WAFI and p27KIPI expression and subsequent inhibition of cyclin-dependent kinases [7]. Some calcium binding proteins are cross-linked at or near plasma membrane into cornified envelope. The effects of calcium are mediated by the protein kinase C pathway, which induces late-differentiation markers (loricrin, profilaggrin) and cornified envelope formation [8]. In the oral cavity, epithelium is continuously bathe in saliva and its composition. We believe that free calcium levels in saliva, maintained by statherin, is important for maintaining the integrity of epithelium by inducing proper differentiation. It is well known that an elevation of cytoplasmic calcium can result from calcium-influx from the extracellular space through a variety of plasma membrane ion channels. More specifically, voltage- and ligand-gated calcium channels in the plasma membrane, along with intracellular ryanodine receptors and inositol (1,4,5)-triphosphate (InsP3) receptors in the endoplasmic reticulum as well as mitochondrial voltage-dependent anion channels and calcium ion exchangers provide fluxes of calcium to the cytoplasm [9]. As a ubiquitous intracellular signaling molecule, calcium is involved in the regulation of almost all cellular functions including gene transcription, metabolism, proliferation and apoptosis [9,10]. Many carcinogenesis related processes such as increased proliferation, decreased differentiation and decreased apoptosis are associated with intracellular calcium concentrations.
http://dx.doi.org/10.1016/j.oraloncology.2014.07.012 1368-8375/Ó 2014 Elsevier Ltd. All rights reserved.
Thus, presence of statherin and its inhibitory aspect of calcium phosphate precipitation creates unique microenvironment in the oral cavity to which oral epithelium is constantly subjected. We proposed that decreased levels of statherin in saliva result in low concentration of free calcium in the oral cavity. Consequently, decreased influx of calcium leads to less availability of intra-cellular calcium causing initiation of carcinogenesis related aforementioned processes. We also believe that such lack of calcium causes less expression of desmosomes junctions (cell adhesion) and cornified envelope enabling an increased penetration of environmental carcinogens through the mucosal surface. We recommend future studies on in vivo salivary calcium influx in the oral epithelia and its role in cellular differentiation and proliferation. Moreover, effects of statherin on intracellular calcium level and its subsequent related molecular alterations would give us new pathogenic aspect in oral carcinogenesis. Conflict of Interest None declared. Funding source None. References [1] Sabatini LM, Carlock LR, Johnson GW, Azen EA. CDNA cloning and chromosomal localization (4q11-13) of a gene for statherin, a regulator of calcium in saliva. Am J Hum Genet 1987;41:1048–60. [2] Schwartz SS, Hay DI, Schluckebier SK. Inhibition of calcium phosphate precipitation by human salivary statherin: structure–activity relationships. Calcif Tissue Int 1992;50:511–7. [3] Johnsson M, Richardson CF, Bergey EJ, et al. The effects of human salivary cystatins and statherin on hydroxyapatite crystallization. Arch Oral Biol 1992;36:631–6. [4] Johansson I, Bratt P, Hay DI, et al. Adhesion of Candida Albicans, built not Candida krusei, to salivary statherin and mimicking host molecules. Oral Microbiol Immunol 2000;15:112–8. [5] Contucci AM, Inzitari R, Agostino S, Vitali A, Fiorita A, Cabras T. Statherin levels in saliva of patients with precancerous and cancerous lesions of the oral cavity: a preliminary report. Oral Dis 2005;11:95–9. [6] Yuspa SH, Kilkenny AE, Steinert PM, Roop DR. Expression of murine epidermal differentiation markers is tightly regulated by restricted extracellular calcium concentrations in vitro. J Cell Biol 1989;109:1207–17. [7] Missero C, Di Cunto F, Kiyokawa H, Koff A, Dotto GP. The absence of p2ICipI/ WAF1 alters keratinocyte growth and differentiation and promotes ras- tumor progression. Genes Dev 1996;10:3065–75. [8] Dlugosz AA, Yuspa SH. Coordinate changes in gene expression which mark the spinous to granular cell transition in epidermis are regulated by protein kinase C. J Cell Biol 1993;120:217–25. [9] Clapham D. Calcium signaling. Cell 2007;131:1047–58. [10] Rizzuto R, Pozzan T. Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 2006;86:369–408.
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Letter to the Editor / Oral Oncology 50 (2014) e55–e56
Sachin C. Sarode Gargi S. Sarode 1 Snehal Patil Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Maheshnagar, Pimpri, Pune – 18, Maharashtra, India Tel.: +91 9922491465. E-mail addresses: [email protected] (S.C. Sarode), [email protected] (G.S. Sarode). Available online 13 August 2014
1
Tel.: +91 9823871462.
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Letter to the Editor Role of Statherin in oral carcinogenesis
Statherin is a protein in humans encoded by the STATH gene. It prevents calcium phosphate precipitation in saliva, thus maintaining a high calcium and phosphate levels [1]. The active region for inhibition of calcium phosphate precipitation resides in 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 maintaining the mineralization of enamel surface [3] and promoting antimicrobial function [4]. There is significant reduction in statherin levels in saliva of precancerous and cancerous lesions of oral cavity. In contrast, non-alteration of statherin levels in inflammatory or salivary gland tumors indicates its exclusive relation with oral cancer and precancer [5]. However, the mechanism of action of statherin in oral carcinogenesis is still remained unanswered. Calcium is an important regulator of epithelial differentiation in vitro. Low concentration calcium causes sustained proliferation and lack of desmosomes. In contrast, at higher calcium levels they express differentiation markers and displays better stratification (through desmosomes) [6]. Moreover, calcium induces a G1 cellcycle arrest that results in part from increased p21WAFI and p27KIPI expression and subsequent inhibition of cyclin-dependent kinases [7]. Some calcium binding proteins are cross-linked at or near plasma membrane into cornified envelope. The effects of calcium are mediated by the protein kinase C pathway, which induces late-differentiation markers (loricrin, profilaggrin) and cornified envelope formation [8]. In the oral cavity, epithelium is continuously bathe in saliva and its composition. We believe that free calcium levels in saliva, maintained by statherin, is important for maintaining the integrity of epithelium by inducing proper differentiation. It is well known that an elevation of cytoplasmic calcium can result from calcium-influx from the extracellular space through a variety of plasma membrane ion channels. More specifically, voltage- and ligand-gated calcium channels in the plasma membrane, along with intracellular ryanodine receptors and inositol (1,4,5)-triphosphate (InsP3) receptors in the endoplasmic reticulum as well as mitochondrial voltage-dependent anion channels and calcium ion exchangers provide fluxes of calcium to the cytoplasm [9]. As a ubiquitous intracellular signaling molecule, calcium is involved in the regulation of almost all cellular functions including gene transcription, metabolism, proliferation and apoptosis [9,10]. Many carcinogenesis related processes such as increased proliferation, decreased differentiation and decreased apoptosis are associated with intracellular calcium concentrations.
http://dx.doi.org/10.1016/j.oraloncology.2014.07.012 1368-8375/Ó 2014 Elsevier Ltd. All rights reserved.
Thus, presence of statherin and its inhibitory aspect of calcium phosphate precipitation creates unique microenvironment in the oral cavity to which oral epithelium is constantly subjected. We proposed that decreased levels of statherin in saliva result in low concentration of free calcium in the oral cavity. Consequently, decreased influx of calcium leads to less availability of intra-cellular calcium causing initiation of carcinogenesis related aforementioned processes. We also believe that such lack of calcium causes less expression of desmosomes junctions (cell adhesion) and cornified envelope enabling an increased penetration of environmental carcinogens through the mucosal surface. We recommend future studies on in vivo salivary calcium influx in the oral epithelia and its role in cellular differentiation and proliferation. Moreover, effects of statherin on intracellular calcium level and its subsequent related molecular alterations would give us new pathogenic aspect in oral carcinogenesis. Conflict of Interest None declared. Funding source None. References [1] Sabatini LM, Carlock LR, Johnson GW, Azen EA. CDNA cloning and chromosomal localization (4q11-13) of a gene for statherin, a regulator of calcium in saliva. Am J Hum Genet 1987;41:1048–60. [2] Schwartz SS, Hay DI, Schluckebier SK. Inhibition of calcium phosphate precipitation by human salivary statherin: structure–activity relationships. Calcif Tissue Int 1992;50:511–7. [3] Johnsson M, Richardson CF, Bergey EJ, et al. The effects of human salivary cystatins and statherin on hydroxyapatite crystallization. Arch Oral Biol 1992;36:631–6. [4] Johansson I, Bratt P, Hay DI, et al. Adhesion of Candida Albicans, built not Candida krusei, to salivary statherin and mimicking host molecules. Oral Microbiol Immunol 2000;15:112–8. [5] Contucci AM, Inzitari R, Agostino S, Vitali A, Fiorita A, Cabras T. Statherin levels in saliva of patients with precancerous and cancerous lesions of the oral cavity: a preliminary report. Oral Dis 2005;11:95–9. [6] Yuspa SH, Kilkenny AE, Steinert PM, Roop DR. Expression of murine epidermal differentiation markers is tightly regulated by restricted extracellular calcium concentrations in vitro. J Cell Biol 1989;109:1207–17. [7] Missero C, Di Cunto F, Kiyokawa H, Koff A, Dotto GP. The absence of p2ICipI/ WAF1 alters keratinocyte growth and differentiation and promotes ras- tumor progression. Genes Dev 1996;10:3065–75. [8] Dlugosz AA, Yuspa SH. Coordinate changes in gene expression which mark the spinous to granular cell transition in epidermis are regulated by protein kinase C. J Cell Biol 1993;120:217–25. [9] Clapham D. Calcium signaling. Cell 2007;131:1047–58. [10] Rizzuto R, Pozzan T. Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 2006;86:369–408.
e56
Letter to the Editor / Oral Oncology 50 (2014) e55–e56
Sachin C. Sarode Gargi S. Sarode 1 Snehal Patil Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Maheshnagar, Pimpri, Pune – 18, Maharashtra, India Tel.: +91 9922491465. E-mail addresses: [email protected] (S.C. Sarode), [email protected] (G.S. Sarode). Available online 13 August 2014
1
Tel.: +91 9823871462.