Ubiquitination is a highly diverse and complex post-translational modification responsible for controlling protein expression and activity in a vast array of cellular processes such as proteasomal degradation, cell cycle regulation, protein trafficking, inflammation and DNA repair [1, 2]. Removal of ubiquitin via the action of deubiquitinating enzymes (DUBs) is integral to the regulation of the ubiquitin system, hence the importance of these enzymes in the maintenance of protein expression and function. There are 5 classes of DUBs and Ubiquitin Carboxyl Terminal Hydrolase-L1 (UCH-L1), a member of the UCH family, catalyses the hydrolysis of ubiquitin from ubiquitin precursors and from ubiquitinated products following proteasomal degradation of polyubiquitinated proteins [3–6]. Therefore UCH-L1 is responsible for conserving the cellular pool of ubiquitin and it has also been implicated in cellular pathways such as proliferation, apoptosis and cell migration . A unique characteristic of UCH-L1 is its ability to act as an ubiquitin ligase in dimeric form, in contrast to acting as a hydrolase in its monomeric form .
UCHL-1 is highly expressed in the central and peripheral nervous system, reproductive tissue and neuroendocrine (NE) cells, although it is expressed in most adult tissues [9, 10]. In both reproductive organs and nervous tissue, UCH-L1 promotes apoptosis. In testicular germ cells UCH-L1 expression is responsible for an early apoptotic wave during spermatogenesis but tight regulation of UCH-L1 is important as high levels cause excessive apoptosis in the ovaries and testes of transgenic mice [5, 11]. In retinal neurons the regulation of intracellular ubiquitin by UCH-L1 alters the stability of pro-apoptotic and anti-apoptotic proteins with a substantial increase in Bcl-2 and XIAP levels in UCH-L1 null mice compared to UCH-L1 wildtype [12, 13]. Aberrant UCH-L1 function in neurons manifests as neurological diseases, such as Parkinson's disease (PD), where dysfunctions of the ubiquitin-proteasome system allow the accumulation of α-synuclein, which is important in the pathology of the disease. Mutations in UCH-L1 have been detected in cases of familial PD. In particular the I93 M amino-acid substitution has been linked to a rare inherited form of PD known as PARK5 [5, 14], whereas the S18Y polymorphism reduces susceptibility to PD .
In cancer, UCH-L1 exhibits highly variable expression patterns seemingly in a tumor-specific manner. UCH-L1 can act as a tumor-suppressor and is silenced in ovarian , hepatocellular [9, 17], renal cell [17, 18], head and neck  and oesophageal carcinomas , when compared to normal tissue. The silencing in many cases is due to hypermethylation of the UCH-L1 promoter region [16, 20–22]. On the contrary, UCH-L1 is over-expressed in neuroblastoma , lung carcinoma, independent of neuronal differentiation , myeloma , prostate carcinoma , osteosarcoma  and pancreatic carcinoma . Several types of cancer present contradictory results in relation to UCH-L1 expression patterns and this is the case in both colorectal and breast carcinoma [16, 29–31].
In non-small cell lung carcinoma (NSCLC) UCH-L1 is consistently highly expressed in both cell lines and primary tumour samples when compared to normal lung tissue where the expression of UCH-L1 is confined solely to cells of the neuroendocrine (NE) system. The presence of high levels of UCH-L1 has also been associated with an advanced tumor stage suggesting a possible role of UCH-L1 in oncogenic transformation and tumor invasion in NSCLC [32, 33]. A correlation has been found between UCH-L1 expression and histological type, with squamous cell carcinomas expressing the protein more frequently than adenocarcinomas [24, 34].
The distinction between different types of NSCLC was until quite recently, clinically unimportant. It was necessary only to decide if a patient had NSCLC or small cell carcinoma, a determination which can be made robustly on morphology. With the development of drugs such as Pemetrexed (Alimta™), which shows more activity against non-squamous NSCLC and Bevacizumab (Avastin™), which is contraindicated for use in squamous cell carcinoma, the further classification of NSCLC type is now the clinical standard. The distinction is made on the basis of morphology, histochemistry (mucin staining with Alcian blue/Periodic acid Schiff) and immunohistochemistry for thyroid transcription factor 1 (TTF-1), cytokeratins (CK) 5/6 and p63 amongst other possible combinations. Squamous differentiation is indicated by positivity with CK5/6 and p63 whilst TTF-1 is negative . Therefore, the differential expression of UCH-L1 in NSCLC has a particular relevance given this impetus for classification of tumor type.
To establish whether UCH-L1 plays an important role in the pathogenesis of lung carcinoma we used two NSCLC cell lines of different subtypes to investigate the phenotypic effects observed following silencing of UCH-L1. We found that UCH-L1 expression increases apoptotic resistance in the adenocarcinoma cell line (H838) and promotes cell migration in the H157 squamous cell carcinoma cell line. Also, in NSCLC tumor samples we showed that UCH-L1 is preferentially expressed in squamous cell carcinoma. To examine the importance of UCH-L1 in patient samples we analyzed NSCLC patient survival data but despite the oncogenic role found in the NSCLC cell lines, no correlation between UCH-L1 expression and survival was evident.