Abstract
Objective To investigate the regulatory effect of ZEB1 on PD-L1 expression and the pharmacodynamic effects of Biochanin A on the malignant biological behaviors of colorectal cancer (CRC). Methods The correlation between epithelial-mesenchymal transition (EMT) score and features of the tumor microenvironment (TME) was investigated using the Cancer Genome Atlas (TCGA) dataset. The correlation between ZEB1 and PD-L1 expression was validated using immunohistochemistry (IHC) staining, and the regulatory effect of ZEB1 on PD-L1 expression was explored by in vitro assays. Moreover, the pharmacodynamic effects of Biochanin A on ZEB1 and PD-L1 expression, as well as malignant biological behaviors of CRC cells, were evaluated by in vitro and in vivo assays. Results EMT score was positively correlated with a majority of immunostimulators, immune checkpoints, activities of antitumor immunity cycles, and infiltration levels of most immune cells in the TCGA dataset. In addition, ZEB1 was correlated with and positively regulated PD-L1 expression in CRC. Besides, Biochanin A, an inhibitor for the ZEB1/PD-L1 axis, notably inhibited ZEB1-mediated aggressiveness and PD-L1 expression of CRC cells. Moreover, Biochanin A also exerted a tumor-inhibitory role in vivo in the CRC mouse model. Conclusion Overall, we found that ZEB1 is a main regulator of PD-L1 expression in CRC. In addition, we also identified Biochanin A as a novel inhibitor for the ZEB1/PD-L1 axis, which could inhibit tumor progression and immune escape.
Highlights
Colorectal cancer (CRC) is one of the most widespread digestive cancers, ranking third in both morbidity and mortality [1]
We explored the correlated pattern of Epithelial-mesenchymal transition (EMT)-related gene expression and features of the tumor microenvironment (TME) utilizing the data from the Cancer Genome Atlas (TCGA) dataset
The immunobiological correlations of EMTenrichment score in CRC were evaluated, which was calculated by single-sample gene set enrichment analysis [10] referring to a penal of EMT-associated genes belonging to gene sets “HALLMARKEPITHELIAL-MESENCHYMAL-TRANSITION” (n 200) in the Molecular Signatures Database (MSigDB) [11]
Summary
Colorectal cancer (CRC) is one of the most widespread digestive cancers, ranking third in both morbidity and mortality [1]. The therapeutic strategies for CRC, including surgery, chemotherapy, radiotherapy, and immunotherapy, have been rapidly and largely developed. Us, the 5-year overall survival (OS) rate for CRC patients has reached 65% and even 90% in early-stage CRC patients [2, 3]. Epithelial-mesenchymal transition (EMT) is a specific biological process in which epithelial cells transform into cells with a mesenchymal phenotype. EMT acts as a significant role in multiple physiological and pathological conditions, such as embryonic development, chronic inflammation, tissue reconstruction, tissue fibrosis, and malignant tumor progression [4]. Rough the EMT process, epithelial cells lose cell polarity, the connection with basement membrane, and other epithelial features but obtain the mesenchymal features, such as high invasive capacity, antiapoptosis, and ability to degrade extracellular matrix [5]. Emerging studies reveal that EMT can significantly promote the progression and immune evasion of malignant tumors
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