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BCAP31, a Cancer/Testis Antigen-Like Protein, Can Act As a Probe for Non www.nature.com/scientificreports OPEN BCAP31, a cancer/testis antigen- like protein, can act as a probe for non-small-cell lung cancer metastasis Jing Wang1,4, Dongbo Jiang1,4, Zichao Li1,4, Shuya Yang1,4, Jiayi Zhou1, Guanwen Zhang1, Zixin Zhang1, Yuanjie Sun1, Zhipei Zhang2, Xiaofei Li2, Liang Tao1, Jingqi Shi1, Yuchen Lu1, Lianhe Zheng3, Chaojun Song1* & Kun Yang1* Non-small-cell lung cancer (NSCLC) represents most of lung cancers, is often diagnosed at an advanced metastatic stage. Therefore, exploring the mechanisms underlying metastasis is key to understanding the development of NSCLC. The expression of B cell receptor-associated protein 31 (BCAP31), calreticulin, glucose-regulated protein 78, and glucose-regulated protein 94 were analyzed using immunohistochemical staining of 360 NSCLC patients. It resulted that the high-level expression of the four proteins, but particularly BCAP31, predicted inferior overall survival. What’s more, BCAP31 was closely associated with histological grade and p53 status, which was verifed by seven cohorts of NSCLC transcript microarray datasets. Then, three NSCLC cell lines were transfected to observe behavior changes BCAP31 caused, we found the fuctuation of BCAP31 signifcantly infuenced the migration, invasion of NSCLC cells. To identify the pathway utilized by BCAP31, Gene Set Enrichment Analysis was frstly performed, showing Akt/m-TOR/p70S6K pathway was the signifcant one, which was verifed by immunofuorescence, kinase phosphorylation and cellular behavioral observations. Finally, the data of label-free mass spectroscopy implied that BCAP31 plays a role in a fundamental biological process. This study provides the frst demonstration of BCAP31 as a novel prognostic factor related to metastasis and suggests a new therapeutic strategy for NSCLC. Lung cancer is one of the most prevalent neoplasms and the leading cause of cancer-related death worldwide, being responsible for nearly one in fve cases1. Non-small-cell lung cancer (NSCLC) contributes to 85% of lung cancer cases. Owing to the absence of clinical symptoms and efective screening programs, most lung cancers are diagnosed at an advanced stage with metastasis. Targeted immunotherapy, including anti-angiogenic and checkpoint monoclonal antibodies or tyrosine kinase inhibitors, demonstrates better efcacy than traditional surgical treatment and radio-chemotherapy, although drug resistance and tumor heterogeneity remain signifcant problems, and metastasis remains the major cause of mortality2. It is therefore important to identify efficient symbolic markers of metastasis and therapeutic targets for NSCLC. Given the aberrant expression of specifc genes in a variety of cancer types, restricted in testis or selected in normal tissue, cancer-testis antigens (CTAs) have emerged as efcient specifc tumor targets which spare nor- mal tissue from incurring damage during treatment3. Originally described in patients with malignant melanoma4, CTAs have been identifed as biomarkers for a diverse range of cancers, including NSCLC5. Teir expression is ofen coordinated6, and associated with poor clinical outcome7 and advanced stage8, particularly metastasis9. Some CTAs have already been used as biomarkers for the diagnosis and prognosis of NSCLC, or as targets in clin- ical trials for vaccine immunotherapy10. According to our previous studies11, B cell receptor-associated protein 31 (BAP31/BCAP31) is a CTA-like protein which is highly expressed in many forms of cancer, including lung cancer. 1Department of Immunology, the Fourth Military Medical University, No.169 Changle W. Rd., Xi’an, 710032, China. 2Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, No.169, Changle W. Rd., Xi’an, 710032, China. 3Department of Orthopedics, Tangdu Hospital; the Fourth Military Medical University, No.169, Changle W. Rd., Xi’an, 710032, China. 4These authors contributed equally: Jing Wang, Dongbo Jiang, Zichao Li and Shuya Yang. *email: [email protected]; [email protected] SCIENTIFIC REPORTS | (2020) 10:4025 | https://doi.org/10.1038/s41598-020-60905-7 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Figure 1. B cell receptor-associated protein 31 (BCAP31) expression in NSCLC and para-carcinoma tissue. (A) RT-PCR analysis of two pairs of NSCLC cancerous tissue samples (C1, C2) and their respective para- carcinoma tissues (P1, P2). (B) Western blot analysis of two pairs of NSCLC cancerous tissue samples (C1, C2) and their respective para-carcinoma tissues (P1, P2). β-actin was chosen as the reference protein for western blotting because of three reports from the Gene Set Enrichment Analysis hinting that tubulin could be afected by BCAP31 (Supplementary Table S2 sheets 1–3). (C) Immunohistochemical analysis for BCAP31, CRT, GRP78, and GRP94 performed on tissues from 360 NSCLC patients. (D) Overall survival curves showing the relevance of the expression of four key protein markers and NSCLC patient overall survival. (E) Te presence of the four markers alone, or in combination, resulted in distinct diferences in the overall survival of NSCLC patients. C: cancer tissue; P: para-carcinoma tissue. All experiments were repeated at least three times. BCAP31, located on chromosome Xq28, encodes a 28 kDa polytopic integral protein of the endoplasmic retic- ulum (ER)12. As an evolutionarily conserved molecule, the BCAP31 protein contains three predicted transmem- brane segments within its amino terminus12, and has been implicated in the sorting of a diverse range of ER membrane proteins, as well as participating in the transportation of various molecules from the ER to the Golgi apparatus13. As a substrate of caspase, BCAP31 participates in the crosstalk between ER and mitochondria to regulate apoptosis14. Afer being defned as a novel CTA-like protein, BCAP31 has been correlated with hepato- cellular carcinoma and breast cancer15,16. However, the relationship between BCAP31 and the development of NSCLC remains unclear. It has been reported that ER proteins can infuence cell growth, migration, and invasion through epithelial-mesenchymal transition (EMT), ER stress, and autophagy17–19. We therefore hypothesized that BCAP31, as an ER chaperone, may play a role in NSCLC metastasis. Tus far, studies have failed to identify a precise mechanism by which BCAP31 can regulate NSCLC cells. To validate our hypothesis, the present study began with an evidence-based medical evaluation and exploration of the molecular mechanisms of BCAP31. To the best of our knowledge, this is the frst study to systematically inves- tigate the signifcance and biological function of BCAP31, and provides new understanding of NSCLC develop- ment and metastasis. Results BCAP31 protein expression correlates with NSCLC. First, we investigated the gene and protein expression of BCAP31. Compared to adjacent tissues, NSCLC tissues had higher levels of both BCAP31 gene and protein expression, as assessed using qRT-PCR and western blot analysis (Fig. 1A,B). To investigate the clinical signifcance of BCAP31 in NSCLC, we examined the expression of three well-known tumor markers, calreticulin (CRT), glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94), as parallel control. Te expression of the four proteins was analyzed immunohistochemically using a tissue microarray of samples from 360 NSCLC patients and16 normal controls. Of the elevated levels of the four proteins (Fig. 1C), BCAP31 was sig- nifcantly associated with histological grade (p = 0.017) (Table 1). At the time of analysis, 137 of the 360 patients were still alive, with a median follow-up of 78 months. Kaplan–Meier survival curves were plotted and Fisher’s exact probability test was performed, which indicated that high expression was associated with patient overall survival (Fig. 1D, Table 2). Retrospective χ2 tests demonstrated that clinicopathological stage and histological grade were risk factors for cancer-related death. Multivariate Cox analysis further demonstrated an enhanced survival prediction of their synergetic efect (Fig. 1E), which implied that BCAP31 could represent a new prog- nostic factor. Analysis of seven transcript expression microarray datasets extracted from the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) validated the positive correlation of BCAP31 expression SCIENTIFIC REPORTS | (2020) 10:4025 | https://doi.org/10.1038/s41598-020-60905-7 2 www.nature.com/scientificreports/ www.nature.com/scientificreports BCAP31 Expression CRT Expression GRP78 Expression GRP94 Expression All High Low High Low High Low High Low Characteristic Patients (n = 223) (n = 137) P (n = 164) (n = 196) P (n = 157) (n = 203) P (n = 231) (n = 129) P Age, years 0.161 0.328 0.35 0.595 Median 58.5 59.6 56.7 59.3 57.9 59.2 58.0 58.8 58.4 Range 28–77 25–77 28–75 34–77 25–75 34–76 25–77 25–76 37–77 Histological type 0.992 0.348 0.811 0.975 Squamous cell 239 148 91 109 130 104 135 157 82 carcinoma Adenocarcinoma 85 53 32 35 50 40 45 56 29 Large cell carcinoma 36 22 14 20 16 17 19 23 13 Clinico-pathologic stage 0.373 0.114 0.007 0.773 I (Ia + Ib) 139 80 59 54 85 44 95 90 49 II (IIa + IIb) 131 86 45 67 64 66 65 89 42 III (IIIa + IIIb) 90 57 33 43 47 39 51 62 28 Tumor size, cm 0.725 0.052 0.185 0.071 <3 35 20 15 10 25 19 16 21 14 3–7 276 174 102 127 149 112 164 182 94 >7 49 29 20 27 22 17 32 24 25 Histological grade 0.017 0.23 0.484 0.543 High (grade 1) 77 47 30 29 48 33 44 52 25 Moderate (grade 2) 164 91 73 73 91 71 93 99 65 Poor (grade 3) 83 64 20 42 41 44 39 57 26 Unidentifed 36 22 14 20 16 17 19 23 13 Nodal status 0.588 0.848 0.25 0.212 N0 198 121 77 94 104 79 119 120 78 N1 97 64 33 43 54 45 52 64 33 N2 65 38 27 29 36 33 32 47 18 Table 1.
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