- // Varda Shoshan-Barmatz 1 , Yael Bishitz 1 , Avijit Paul 1 , Yakov Krelin 1 , Itay Nakdimon 1 , Nir Peled 2 , Avia Lavon 1 , Elina Rudoy-Zilberman 3 and Yael Refaely 3 1 Department of Life Sciences and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel 2 Thoracic Cancer Unit and The Center for Precision Cancer Care, Davidoff Cancer Center, Petach Tiqwa, Israel 3 Department of Cardio-Thoracic Surgery, Soroka University Medical Center and The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel Correspondence to: Varda Shoshan-Barmatz, email: firstname.lastname@example.org Keywords: biomarkers; lung cancer; adenocarcinoma and squamous cell carcinoma Received: July 12, 2017 Accepted: August 17, 2017 Published: November 06, 2017 ABSTRACT Adenocarcinoma (AC) and squamous cell carcinoma (SCC), sub-types of non-small cell lung cancer (NSCLC), both present unique features at the genome, epigenome, transcriptome and proteome levels, as well as shared clinical and histopathological characteristics, but differ in terms of treatment. To ensure proper treatment, one must be able to distinguish between these sub-types. Here, we identify novel biomarker proteins in NSCLC, allowing for distinguishing between the AC and SCC sub-types. Proteomics analysis distinguished between healthy and tumor tissues, with the expression level of 1,494 proteins being altered, 378 of which showed a ≥|100|-fold change. Enrichment of proteins related to protein synthesis and degradation, and of proteins associated with mitochondria, metabolism, and apoptosis, was found. Network analysis defined groups of proteins, such as those associated with cell metabolic processes or with fatty acid/lipid metabolism and transport. Several biomarkers that enable for distinguishing between AC and SCC were identified here for the first time, and together with previous reports confirmed here, led us to propose a list of proteins differentially expressed in SCC and AC. Some of these biomarkers are clear signatures for AC or SCC and four of them are secreted proteins. The presence of the mitochondrial protein SMAC/Diablo in the nucleus was found to be a signature for SCC. Precise diagnosis of AC and SCC is essential for selecting appropriate treatment and thus, increasing patient life expectancy. Finally, the search for drugs that target some of these biomarkers may lead to new treatments for lung cancer.