Systematic molecular analysis of the human secretome and membrane proteome in gastrointestinal adenocarcinomas.

Abstract

The human secretome and membrane proteome are a large source of cancer biomarkers. Membrane‐bound and secreted proteins are promising targets for many clinically approved drugs, including for the treatment of tumours. Here, we report a deep systematic analysis of 957 adenocarcinomas of the oesophagus, stomach, colon and rectum to examine the cancer‐associated human secretome and membrane proteome of gastrointestinal tract adenocarcinomas (GIACs). Transcriptomic data from these GIACs were applied to an innovative majority decision‐based algorithm. We quantified significantly expressed protein‐coding genes. Interestingly, we found a consistent pattern in a small group of genes found to be overexpressed in GIACs, which were associated with a cytokine–cytokine interaction pathway (CCRI) in all four cancer subtypes. These CCRI associated genes, which spanned both one secretory and one membrane isoform were further analysed, revealing a putative biomarker, interleukin‐1 receptor accessory protein (IL1RAP), which indicated a poor overall survival, a positive correlation with cancer stemness and a negative correlation with several kinds of T cells. These results were further validated in vitro through the knockdown of IL1RAP in two human gastric carcinoma cell lines, which resulted in a reduced indication of cellular proliferation, migration and markers of invasiveness. Following IL1RAP silencing, RNA seq results showed a consistent pattern of inhibition related to CCRI, proliferation pathways and low infiltration of regulatory T cells (Tregs) and CD8 naive cells. The significance of the human secretome and membrane proteome is elucidated by these findings, which indicate IL1RAP as a potential candidate biomarker for cytokine‐mediated cancer immunotherapy in gastric carcinoma.