Identification and validation of xenobiotic metabolism-associated prognostic signature based on five genes to evaluate immune microenvironment in colon cancer

Abstract

Background: Xenobiotic metabolism plays an important role in the progression of colon cancer; however, little is known about its related biomarkers. This study sought to construct a prognostic model related to xenobiotic metabolism in colon cancer, and further reveal the characteristics of tumor immune microenvironment based on the prognostic model. Methods: Transcriptome data of 41 normal colon tissues and 473 colon tumor tissues and the clinical features of 452 colon cancer patients were downloaded from The Cancer Genome Atlas (TCGA) database.Data on xenobiotic metabolism genes (XMGs) were obtained from the hallmark xenobiotic metabolism set of the Molecular Signatures Database (MSigDB) and articles. Additionally, data on differential XMGs in colon cancer were acquired for a functional enrichment analysis by R software. An XMG prognostic model was constructed by a Cox regression analysis, and evaluated using Kaplan-Meier survival curves, risk curves, receiver operating characteristic (ROC) curves, and an independent prognostic analysis in a training cohort and validation cohort. Moreover, tumor immune infiltration and negative regulatory immune genes of cancer-immunity cycle (CIC), including immune checkpoints and immune cytokines, were further analyzed between low-and high-risk groups in both the training and validation cohorts. Differences with P value <0.05 were interpreted as statistically significant.Results: A total of 126 differential XMGs were distinguished in the colon cancer data set, which were mainly enriched in the metabolism pathways of drugs and nutrients. There were 5 optimized genes (i.e., CYP2W1, GSTM1, TGFB2, MPP2, and ACOX1) used to construct the prognosis model, which effectively predicted prognosis and had good ROC curves. Between low-and high-risk groups, there were significant differences in abundance for T cells CD4 memory resting and T cells regulatory (Tregs), and expression of PDCD1, LAG3, NOS3, TGFB1, and ICAM1 in the training cohort and validation cohort. Conclusions: The XMGs in the prognostic model have a good prediction effect on the prognosis of colon cancer patients. The T cells CD4 memory resting, and Tregs, immune checkpoints PDCD1 and LAG3, and CIC negative regulatory immune cytokines NOS3, TGFB1, and ICAM1 are closely associated with xenobiotic metabolism.

Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes β-catenin palmitoylation to drive colorectal cancer progression

“…In addition, ACOX1 acts as a target gene of mir-15B-5p to inhibit tumor cell metastasis 14 . These studies indicate the inhibitory role of ACOX1 in cancer [11][12][13][14][15] . However, the role of metabolic reprogramming caused by dysregulation of the metabolic enzyme ACOX1's post-translational modification in colorectal cancer (CRC) remains elusive.…”

Increased Kremen2 predicts worse prognosis in colon cancer

“…Kremen2 plays a crucial role in neural crest induction (11), bone formation (12,21), and tumorigenesis (8,22). Kremen2 inhibits cell apoptosis by inhibiting homodimerisation of Kremen1.…”

“…R packages “ggpubr” and “limma” were used to compare Kremen2 mRNA expression between the colon tumour and normal tissue samples ( 13 ). On the basis of the levels of Kremen2 mRNA expression in tumour tissues, 316 patients were subsequently enrolled and separated into two groups (the high-expression and low-expression groups).…”

“…Kremen2 involvement in the development of the embryo, bone, neural ridge, and tumours has been demonstrated by several studies (11,12). According to The Cancer Genome Atlas (TCGA) data, more than 65% of the tissue samples in 18 different types of cancer, revealed that Kremen2 expression in cancerous tissues was greater in comparison to that in paired normal tissues.…”

Breast Cancer Exposomics

“…In addition, the gut absorbs dietary nutrients and provides a barrier to many xenobiotics and microbiome-derived metabolites, so the intestinal epithelium becomes one of the most rapidly proliferating tissues in the body, assuring a rapid and effective elimination of some xenobiotics that bioaccumulate in enterocytes [ 90 ]. Consequently, the gastro-intestinal tract is also an important route by which drugs, chemicals, pesticides, environmental pollutants, and metabolites of other species are absorbed in the human body [ 91 ]. Last but not least, air pollution is known as a human carcinogen, especially by gaseous components, as well as through particulate matter, including fine, inhalable particles that can be vectors for radioactive isotopes [ 92 , 93 ].…”