Abstract
Epithelial-mesenchymal transition (EMT) is involved in various tumor processes, including tumorigenesis, tumor cell migration and metastasis, tumor stemness, and therapeutic resistance. Therefore, it is important to identify the genes most associated with EMT and develop them as therapeutic targets. In this work, we first analyzed EMT hallmark gene expression profiles among 10,535 pan-cancer samples from The Cancer Genome Atlas (TCGA) and divided them into EMT high and EMT low groups according to the metagene scores. Then, we identified 12 genes that were most associated with high EMT metagene score (R > 0.9) in 329 colon adenocarcinoma (COAD) patients. Among them, only 4 genes (AEBP1, KCNE4, GFPT2, and FAM26E) had statistically significant differences in prognosis (P < 0.05). Next, we selected AEBP1 as a candidate and showed that AEBP1 mRNA levels and EMT biomarkers strongly coexpressed in 329 COAD samples. In addition, AEBP1 was highly expressed and associated with poor clinical outcomes and prognosis in COAD patients. Finally, to explore whether AEBP1-mediated EMT was related to the tumor microenvironment (TME), we examined AEBP1 expression levels at the single-cell levels. Our results showed that AEBP1 levels were extremely high in tumor-associated fibroblasts, which may induce EMT. AEBP1 expression was also positively correlated with the expression of fibroblast biomarkers and also with EMT metascores, suggesting that AEBP1-mediated EMT may be associated with the stimulation of fibroblast activation. Therefore, AEBP1 may be a promising target for EMT inhibition, which reduces cancer metastasis and drug resistance in COAD patients.
Highlights
Colon adenocarcinoma (COAD) is characterized by late onset, rapid tumor progression, and heterotopic metastasis, and it is the third leading cause of cancer-related deaths in the world [1]
Heatmap showed the expression pattern from the 200 Epithelial-mesenchymal transition (EMT) genes based on EMT metagene scores; the groups were divided into EMT high and EMT low groups according to the metagene scores (Figure 1(a))
These 200 genes were all highly expressed in the EMT high score group, indicating that the EMT high score could provide a good representation of the EMT pathway being activated (Figure 1(a))
Summary
Colon adenocarcinoma (COAD) is characterized by late onset, rapid tumor progression, and heterotopic metastasis, and it is the third leading cause of cancer-related deaths in the world [1]. Despite the application of targeted drugs and immunosuppressive agents that extend the survival of patients, there is still a need to overcome metastasis and treatment resistance in COAD. EMT has been involved in a variety of tumor characteristics, including tumorigenesis, malignant progression, tumor cell migration and metastasis, blood intravasation, tumor stemness, and therapeutic resistance [4,5,6]. The evidence is overwhelming, on the other hand, that cancer progression and metastasis initiate in cells with the majority of stem cell characteristics, termed cancer stem cells (CSCs) [7]. CSCs are known to be able to self-renew and divide asymmetrically. These cells contribute to tumorigenesis, expansion, resistance, metastasis, and recurrence after treatment [8]. Increased evidence suggests a strong association between EMT and the production of CSCs [11]
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