LCK, survivin and PI-3K in the molecular biomarker profiling of oral lichen planus and oral squamous cell carcinoma

Abstract

T cell signaling is critical in oral lichen planus (OLP) based on the pathogenesis of this chronic inflammatory autoimmune mucocutaneous lesion. Lck plays a key role in T cell signaling; ultimately this signaling affects other targets such as PI-3K. Excessive activity in PI-3K inhibits apoptosis and promotes uncontrolled cell growth. Molecular biomarker profiling in OLP, Chronic Interface Mucosities (CIM), Epithelial Dysplasia (EpD) and Oral Squamous Cell Carcinoma (SCCA) with application of the principle of biomarker voting may represent a new frontier in the diagnosis, assessment and the arguable debate of OLP transformation to cancer. The presence of Lck, PI-3K and Survivin, a cancer specific anti-apoptotic protein was assessed, using immunohistochemistry and tissue micro-array on patient samples, in OLP, SCCA, CIM and EpD. Lck expression was very high in 78.6 % of OLP patients compared to 3.7% in SCCA; PI-3K was high in 63% of SCCA, 100% of EpD, and 35.7% OLP cases. Survivin was high in 64.3% of OLP cases, 96.3% of SCCA, and 100% of EpD. CIM cases may be slightly different molecularly to OLP. Taken together, our data suggest that biomarker protein voting can be effectively used to isolate high-risk OLP cases. Specifically, we show data with four remarkable cases demonstrating that molecular factors are predictive of histopathology. We conclude that it is safer to treat OLP as premalignant lesions, to adopt aggressive treatment measure in histopathologic described well and moderately differentiated SCCA, and to monitor progress of these diseases molecularly using individualized auto-proteomic approach. The use of Lck inhibitors in OLP management needs to be investigated in the future.

The role of the microenvironment in tumor immune surveillance

“…Similar arguments stand for the increase rate of cancer transformation from the two distinct forms of OPM, epithelial dysplasia (EpD) and erythroplakia, compared to leukoplakia [19]. A case in point pertains to our data, which showed that OPM cases of EpD revealed similar molecular signatures with OSCC cases [10]. …”

“…Molecular proteomic profiling, such as our work [10], further indicates that OLP, OPM, OSCC and other oral and pharyngeal cancers may benefit from therapy based on inhibitors of PI-3k, Lck, and related signaling pathways, used as single or multi-drug therapy. It is our contention here that a principal mode of action of these interventions is to target specific events modulated by T cells subpopulations, and driven by the microenvironment, such as, for instance, the use of anti-Lck to control inflammation, cancer progression and metastasis, or the use of PI-3k inhibitors in modulating the microenvironment to subdue tumor transformation and proliferation in oral premalignant lesions such as epithelial dysplasia.…”

“…Lck, a src tyrosine kinase, acts downstream of the TCR complex to regulate T-cell signaling. OLP biopsy samples show robust expression of Lck [10], which suggests that the chronic inflammatory nature of the microenvironment in OLP might be reduced by targeting T cell signaling, and specifically the pivotal role of Lck (Figure 3). Such therapeutic measures may curtail the impact of T cell plasticity and subsets signatures of cytokines, while minimizing inhibition of basic physiological activities.…”

“…These interventions have not been tested in the context of the oral pathologies discussed here. However, based on the novel perspectives explored above [4] and our own data [10] we argue that PI-3k inhibitors may soon find effective therapeutic use in the treatment of premalignant oral lesions, including OLP. Considering the adoption of these drugs in the armamentarium for treating premalignant oral lesions will improve the current understanding of the molecular efficacy of these drugs, and their mechanisms of action as well as resistance, and ultimately lead to improved treatment.…”

Clinical and Genetic Aspects of Oral Lichen Planus

“…However, these studies were in most cases dealing with one single gene or with a single gene family. [36][37][38][39][40][41][42][43][44] However, only few of them have a high number of interactions with the other genes in the network and therefore they may play a major role. These genes were identified and termed as ""leader genes"".…”