Abstract
The chemokine ligand C-X-C motif chemokine ligand 11 (CXCL11) is involved in the progression of various cancers, but its biological roles in colorectal cancer (CRC) remain confused. Therefore, the prognostic value and underlying mechanism of CXCL11 in CRC were preliminarily evaluated. Three independent datasets were used for mRNA-related analysis: one dataset from the Cancer Genome Atlas (TCGA, n = 451) and two single-cell RNA sequencing (scRNA-seq) datasets from Gene Expression Omnibus (GEO): GSE146771 and GSE132465. In addition, a colon adenocarcinoma (COAD) patient cohort (the Yijishan Hospital cohort, YJSHC, n = 108) was utilized for analysis of cell infiltration by immunohistochemistry. We determined the distribution of CXCL11 in tumor tissue across all TCGA cancers and found that CXCL11 expression was significantly upregulated in both COAD and rectal adenocarcinoma (READ). However, the upregulation of CXCL11 mRNA was associated with a better prognosis in COAD, but not in READ. Within the YJSHC, the patients with a high abundance of intratumoral CXCL11+ cells had prolonged survival (p = 0.001). Furthermore, we found that the high CXCL11 expression group had a higher proportion of antitumor immune cells, and a lower proportion of protumor immune cells. Additionally, we discovered the changes of gene expression and enriched immune pathway network mediated by CXCL11. Interestingly, both cytotoxic genes (IFNG, GZMA, GZMB, GZMK, GZMM, and PRF1) and immunosuppressive molecules, including PD-L1, were positively correlated with CXCL11 expression. CXCL11, which promoted antitumor immunity to benefit survival, was identified as an independent prognostic biomarker in patients with COAD.
Highlights
Colorectal cancer (CRC) is a commonly occurring cancer and remains the third leading cause of cancer-related death worldwide (Arnold et al, 2017)
We evaluated the distribution of CXCL11 in tumor tissue across all TCGA cancers in TIMER and found that CXCL11 expression was significantly upregulated in the majority of tumors, including colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) (Figure 1A)
TISIDB was utilized to examine the association between CXCL11 and clinical outcome across all TCGA tumors, and we found that COAD patients but not READ patients with high mRNA expression of CXCL11 had a better prognosis, instead of READ (Figure 1B)
Summary
Colorectal cancer (CRC) is a commonly occurring cancer and remains the third leading cause of cancer-related death worldwide (Arnold et al, 2017). The molecular mechanisms underlying CRC development should be further explored, and novel biomarkers for prognostic evaluation should be identified. Evidence suggests the involvement of the tumor microenvironment (TME), especially immune cells, in the development of CRC in addition to genetic mutations The distinct roles of antitumor immunity are dependent on cytokine-cytokine interactions, which constitute the cytokine networks that normally maintain intestinal homeostasis (West et al, 2015). As a family of small signaling cytokines, chemokines are a very important part of the cross talk between tumor cells and the microenvironment, and these molecules interact with their receptors to regulate the leukocyte infiltration, tumor related angiogenesis, host immune response activation and tumor cell proliferation (Cabrero-de, Las Heras and Martínez-Balibrea, 2018)
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