Role Of Sphingosine 1 Phosphate Signaling Pathway In Oral Squamous Cell Carcinoma

Abstract

Due to the increasing incidence rate of OSCC in India, it became a major health problem in the country. Tobacco came out to be the main risk factor for OSCC in men. Due to the limitations in the current treatment modalities, there was a need to identify some molecular targets.S1P signaling plays a crucial role in the regulation of various processes of tumorigenesis in variety of cancers. The mRNA and protein expression of their eight S1P metabolizing enzyme (SphK1/2, SGPL1, SGPP1/2 and LPP1-3) by qRTPR and Immunohistochmeistry respectively, was determined in OSCC patients and 4NQO induced TSCC mouse model. The downregulation of expression of SphK2 and LPP3 in OSCC tumors was a prominent finding. High expression of SphK1 both at mRNA and protein levels in OSCC patients as well as in tongue tumors from TSCC mouse model turns out to be targetable kinase .The results in mouse model of tongue carcinogenesis suggest that induction of SphK1 expression begins in the very early stage of oral carcinogenesis. Here, the decreased expression of SphK2 was determined for the first time in OSCC. The increased expression of SphK2 at the pre-neoplastic stage and the decreased expression in the later stages in the TSCC of mouse reveal that SphK2 might have a biphasic role. In the early stage it may promote oral carcinogenesis, where as in the later stage it may suppress tumorigenesis. Consistent to studies on OSCC patients, this study reveals that LPP3 is expressed as a high level in the normal mouse tongue epithelium, whereas its expression was decreased in dysplastic tongue from 4NQO-treated mice. Increased expression of SphK1 and decreased expression of LPP3 leads to increased levels of S1P in the plasma and tongue tissue of mouse as compared to control. Long non-coding RNA s also playing an important role in OSCC. Among 5-lncRNA, studied, H19 was prominently downregulated in OSCC patients. In addition to S1P, other lipids like phosphatidylglycerol sphingomyelin {SM(d18:1/18:3)}, phosphatidyl inositol phosphate {PIP(31:4/22:5)}