cancers Article GCC2 as a New Early Diagnostic Biomarker for Non-Small Cell Lung Cancer Hyesun Jeong 1,2,† , Byeong Hyeon Choi 3,4,† , JinA Park 1,2 , Jik-Han Jung 5 , Hyunku Shin 6 , Ka-Won Kang 7 , Yu Hua Quan 4,8 , Jewon Yu 9 , Ji-Ho Park 5 , Yong Park 7 , Yeonho Choi 2,6 , Hyun Koo Kim 4,8, * and Sunghoi Hong 1,2, *   Citation: Jeong, H.; Choi, B.H.; Park, J.; Jung, J.-H.; Shin, H.; Kang, K.-W.; Quan, Y.H.; Yu, J.; Park, J.-H.; Park, Y.; et al. GCC2 as a New Early Diagnostic Biomarker for Non-Small Cell Lung Cancer. Cancers 2021, 13, 5482. https://doi.org/10.3390/ cancers13215482 Academic Editor: Carlos S. Moreno Received: 29 September 2021 Accepted: 28 October 2021 Published: 31 October 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 School of Biosystems and Biomedical Sciences, Korea University, Seoul 02841, Korea; lullaby0810@gmail.com (H.J.); 2020020815@korea.ac.kr (J.P.) 2 BK21 FOUR R&E Center for Precision Public Health, Graduate School of Korea University, Seoul 02855, Korea; yeonhochoi@korea.ac.kr 3 Korea Artificial Organ Center, Korea University, Seoul 02841,Korea; baby2music@gmail.com 4 Department of Thoracic and Cardiovascular Surgery, Korea University Guro Hospital, College of Medicine, Korea University, Seoul 08308, Korea; hwa1983418@gmail.com 5 Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea; jjhan@kaist.ac.kr (J.-H.J.); jihopark@kaist.ac.kr (J.-H.P.) 6 Department of Bio-Convergence Engineering, Korea University, Seoul 02841, Korea; ramgee91@gmail.com 7 Department of Internal Medicine, Division of Hematology-Oncology, Korea University College of Medicine, Seoul 02841, Korea; ggm1018@gmail.com (K.-W.K.); paark76@korea.ac.kr (Y.P.) 8 Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Korea 9 Exopert Corporation 4th Floor, Seoul 02580, Korea; jewon@exopert.com * Correspondence: kimhyunkoo@korea.ac.kr (H.K.K.); shong21@korea.ac.kr (S.H.) † These authors are equally contributed to this work. Simple Summary: Lung cancer, including non-small cell lung cancer, is the leading cause of cancer- related death worldwide. A better prognosis is associated with early diagnosis of lung cancer patients. Although annual screening guidelines for lung cancer are recommended, using various tools such as chest X-ray, low-dose computed tomography, and positron emission tomography, these screening procedures are expensive and difficult to repeat. They are also invasive and have a high risk of radiation exposure. Therefore, a low-risk, convenient diagnostic method using liquid biopsy and biomarkers is required for the early diagnosis of lung cancer. The newly proposed biomarker GCC2 was identified through proteomic analysis of exosomes secreted from lung cancer cell lines. GCC2 expression levels in peripheral blood of the patients showed high specificity and sensitivity in early lung cancer, demonstrating that our novel exosomal biomarker GCC2 can greatly contribute to improving the diagnosis of lung cancer patients, even though it has been tested in only a few pilot studies. Abstract: No specific markers have been identified to detect non-small cell lung cancer (NSCLC) cell-derived exosomes circulating in the blood. Here, we report a new biomarker that distinguishes between cancer and non-cancer cell-derived exosomes. Exosomes isolated from patient plasmas at various pathological stages of NSCLC, NSCLC cell lines, and human pulmonary alveolar epithelial cells isolated using size exclusion chromatography were characterized. The GRIP and coiled-coil domain-containing 2 (GCC2) protein, involved in endosome-to-Golgi transport, was identified by proteomics analysis of NSCLC cell line-derived exosomes. GCC2 protein levels in the exosomes derived from early-stage NSCLC patients were higher than those from healthy controls. Receiver operating characteristic curve analysis revealed the diagnostic sensitivity and specificity of exosomal GCC2 to be 90% and 75%, respectively. A high area under the curve, 0.844, confirmed that GCC2 levels could effectively distinguish between the exosomes. These results demonstrate GCC2 as a promising early diagnostic biomarker for NSCLC. Keywords: exosomes; non-small cell lung cancer; GCC2; biomarkers; early detection; liquid biopsy; cancer Cancers 2021, 13, 5482. https://doi.org/10.3390/cancers13215482 https://www.mdpi.com/journal/cancers