Protein profiling reveals the characteristic changes of complement cascade pathway in the tissues of gastric signet ring cell carcinoma

Abstract

39Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer that has 40 distinct features in cellular morphology, epidemiology and clinicopathology compared 41 with adenocarcinomas (ACs). Lacking of systematically molecular overview to this 42 disease made a slow progress in diagnosis and therapy for SRCC. In the present 43 proteomics study, the gastric tissues were collected from tumor and adjacent regions 44including 14 SRCC and 34 AC cases, and laser capture microdissection (LCM) was 45 employed to eradicate cellular heterogeneity of the tissues. Over 6,000 proteins were 46 quantified through data independent acquisition (DIA) mass spectrometry (MS). The 47 quantitative profiles of proteomes in tumor tissues, either AC or SRCC, were 48 dramatically different from that in the corresponding adjacencies, whereas the SRCC 49 proteomes appeared not distinguishable to the AC proteomes via hierarchical clustering. 50However, focusing on univariate analysis and pathway enrichment unrevealed that 51 some proteins and pathways bared the differences between SRCC and ACs. Importantly, 52the abundance changes for a bulk of proteins involved in complement cascade were 53highly associated with SRCC but not so sensitive to the AC status. A hypothesis, 54therefore, was proposed that the complement cascade was evoked in the SRCC 55 microenvironment upon infiltration, while the SRCC cells survived from the 56 complement cytotoxicity by secreting negative regulators. Moreover, an attempt was 57 made to seek appropriate cell model for gastric SRCC, through proteomic comparison 58 of the 15 gastric cell lines and the gastric tumors. The prediction upon supervised 59 classifier suggested none of these gastric cell lines qualified in mimic to SRCC. 60 61 65 predominantly or exclusively of signet-ring cells, which are characterized by a central 66 optically clear, globoid droplet of cytoplasmic mucin with an eccentrically placed 67 nucleus 1 . On the contrary to a trend of decreasing incidence of gastric cancer worldwide, 68the SRCC incidence has remained rising 2 . The molecular features of pathology and 69 pharmacology relevant to SRCC are highly attractive in the frontier of gastric cancer 70 study. 71 72Gastric SRCC is not only special in its histology, but is also very different in 73 clinicopathological features from other subtypes of gastric cancer. The female incidence 74 of SRCC in all the gastric cancer is approximately 50%, whereas that of non-SRCC is 75 about 30%; the average incidence age of SRCC is around 62 years, whereas that of non-76 SRCC is roughly 69 years 3 . Although Helicobacter pylori infection is regarded as a risk 77 factor to gastric cancer, this bacterium is not commonly found in SRCC 4 . With 78comparison of SRCC to other two main subtypes of gastric cancer, well-moderately 79 differentiated adenocarcinoma (WMDAC) and poorly differentiated adenocarcinoma 80 (PDAC), Chon et al observed that at early stage the prognosis of SRCC was better than 81 that of WMDAC and PDAC, whereas at later s...