Pan-cancer analysis shows that BCAP31 is a potential prognostic and immunotherapeutic biomarker for multiple cancer types

Abstract

Background: B-cell receptor-associated protein 31 (BCAP31) is a widely expressed transmembrane protein primarily located in the endoplasmic reticulum (ER), including the ER-mitochondria associated membranes. Emerging evidence suggests that BCAP31 may play a role in cancer development and progression, although its specific effects across different cancer types remain incompletely understood.

Methods: The raw data on BCAP31 expression in tumor and adjacent non-tumor (paracancerous) samples were obtained from the Broad Institute Cancer Cell Line Encyclopedia (CCLE) and UCSC databases. We also examined the association between BCAP31 expression and clinicopathological factors. Using the Cox proportional hazards model, we found that high BCAP31 levels were linked to poor prognosis. To further explore BCAP31's role, we analyzed the relationship between copy number variations (CNV) and BCAP31 mRNA expression using data from The Cancer Genome Atlas (TCGA). Additionally, the association between BCAP31 expression and signature pathway scores from the MsigDB database provided insights into the tumor biology and immunological characteristics of BCAP31.We assessed the relationship between tumor immune infiltration and BCAP31 expression using the TIMER2 and ImmuCellAI databases. The ESTIMATE computational method was employed to estimate the proportion of immune cells infiltrating the tumors, as well as the stromal and immune components, based on TCGA data. To investigate drug sensitivity in relation to BCAP31 expression, we utilized GDSC2 data, which included responses to 198 medications. We explored the relationship between BCAP31 gene expression and response to immunotherapy. Additionally, the study involved culturing KYSE-150 cells under standard conditions and using siRNA-mediated knockdown of BCAP31 to assess its function. Key experiments included Western blotting (WB) to confirm BCAP31 knockdown, MTT assays for cell proliferation, colony formation assays for growth potential, Transwell assays for migration and invasion, and wound healing assays for motility. Additionally, immunohistochemistry (IHC) was performed on tumor and adjacent normal tissue samples to evaluate BCAP31 expression levels.

Results: BCAP31 was found to be significantly overexpressed in several prevalent malignancies and was associated with poor prognosis. Cox regression analysis across all cancer types revealed that higher BCAP31 levels were predominantly linked to worse overall survival (OS), disease-free interval (DFI), disease-specific survival (DSS), and progression-free interval (PFI). In most malignancies, increased BCAP31 expression was positively correlated with higher CNV. Additionally, BCAP31 expression was strongly associated with the tumor microenvironment (TME), influencing the levels of infiltrating immune cells, immune-related genes, and immune-related pathways. Drug sensitivity analysis identified six medications that showed a significant positive correlation with BCAP31 expression. Furthermore, BCAP31 expression impacted the outcomes and prognosis of cancer patients undergoing immune therapy. The functional assays demonstrated that BCAP31 knockdown in KYSE-150 cells significantly inhibited cell migration, invasion, and proliferation while enhancing colony formation ability. WB and immunohistochemistry analyses confirmed elevated BCAP31 expression in tumor tissues compared to adjacent normal tissues in esophageal cancer, lung adenocarcinoma, and gastric adenocarcinoma.

Conclusion: BCAP31 has the potential to serve as a biomarker for cancer immunology, particularly in relation to immune cell infiltration, and as an indicator of poor prognosis. These findings provide a new perspective that could inform the development of more targeted cancer therapy strategies.

Keywords: BCAP31; biomarker; pan-cancer; prognosis; target therapy.