Purpose: Previous studies found that gap junction alpha-1 protein (GJA1) was a potent tumor suppressor in colorectal cancer (CRC). We designed the present study to evaluate the clinical importance and molecular mechanisms of GJA1 in CRC.
Methods: Clinical and transcriptomic data from TCGA and GEO datasets were retrospectively collected. CRC patients were divided into two subgroups according to the expression level of GJA1 mRNA. Difference between survival time and response to neoadjuvant chemotherapy was then evaluated. Functional assays including wound-healing assay, transwell invasion assay and flow cytometry assay were performed to investigate the effects of GJA1 on invasive ability and response to chemotherapy drugs of CRC cells. Moreover, we explored the mechanisms of GJA1 by which it regulates CRC malignant phenotypes.
Results: The expression level of GJA1 was significantly higher in normal tissue than cancer tissue, indicating a tumor suppressive role of GJA1 in CRC. Patients with higher expression of GJA1 showed better prognosis than those with low GJA1 expression level. Consistently, overexpression of GJA1 suppressed the invasive ability of CRC cells while enhancing the sensitivity of CRC cells to oxaliplatin-induced apoptosis. Mechanically, we found that GJA1 suppressed the epithelial mesenchymal transition process. Moreover, GJA1 could modulating infiltrating levels of several immune cells in the tumor microenvironment.
Conclusion: These findings suggested that GJA1 was correlated with prognosis and immune infiltrating levels of CD8+ T cells, macrophages, neutrophils, and DCs in CRC. In addition, GJA1 expression contributes to regulation of tumor-associated macrophages (TAMs) and tumor infiltrating neutrophils (TINs) in CRC. These findings suggest that GJA1 is a promising biomarker for determining prognosis and immune infiltration in colorectal cancer.
Keywords: chemotherapy; colorectal cancer; immune infiltrates; metastasis; the gap junction channel protein.