The Epithelial to Mesenchymal Transition Related Gene Calumenin Is an Adverse Prognostic Factor of Bladder Cancer Correlated With Tumor Microenvironment Remodeling, Gene Mutation, and Ferroptosis

Abstract

The tumor microenvironment (TME) plays a critical regulatory role in bladder cancer (BLCA) progression and metastasis. Epithelial-mesenchymal transition (EMT) presents as an essential mechanism of tumor invasion and metastasis. Accumulating pieces of evidence indicated that several microenvironmental factors, including fibroblasts, endothelial, and immune cells, induced EMT in tumor cells. As a hallmark gene of the EMT process, calumenin (CALU) was previously reported to directly impact cancer metastasis. However, the functions and molecular mechanisms of CALU have been rarely reported in BLCA. By multi-omics bioinformatics analysis of 408 TCGA BLCA patients, we demonstrated that CALU was an independent risk factor for BLCA outcome. Subsequently, we verified the correlation of CALU with cancer-associated fibroblasts (CAFs) and tumor-infiltrating immune cells. The results suggested a positive correlation of CALU with CAFs, CD8+ T cells and macrophages. Also, CALU was significantly associated with multiple immune checkpoint-related genes, which ultimately influenced patients’ responsiveness to immunotherapy. Further, we found that the impact of CALU on BLCA prognosis might also be correlated with gene mutations and ferroptosis. Finally, we validated the roles of CALU by single-cell RNA sequencing, PCR and immunohistochemistry. In conclusion, we found that CALU affected BLCA prognosis associated with multiple mechanisms, including TME remodeling, gene mutation and ferroptosis. Further studies on CALU may provide new targets for BLCA immunotherapy and precision medicine.

Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment

“…Moreover, it has been shown that EGF, hepatocyte growth factor (HGF), bFGF, and PDGF are also involved in the induction of transcription factors responsible for EMT progression [277,278,372,373]. EMT signatures are inversely correlated with T-cell infiltration in NSCLC, urothelial cancer and with resistance to PD-1 blockade in melanoma [279,[374][375][376]. However, a few recent studies showed a positive correlation between T-cell infiltration and stromal EMT-related gene expression, in various malignancies [377,378].…”

Five EMT‐related genes signature predicts overall survival and immune environment in microsatellite instability‐high gastric cancer

“…CALU (Calumenin), as a pivotal gene of the EMT process, has been reported to directly link to the cancer metastasis of a variety of cancers 43–45 . CALU may be involved in tumor microenvironment remodeling because of its close association with CD8 cells and macrophages 46,47 . PLOD2 (2‐oxoglutarate 5‐dioxygenase 2), an intracellular enzyme belonging to the PLOD family, plays a critical role in collagen modification, cell migration, and pulmonary metastasis with no impact on primary tumor growth 48,49 .…”

Single-Cell RNA-Seq Reveals the Promoting Role of Ferroptosis Tendency During Lung Adenocarcinoma EMT Progression

“…Protein LYRIC can promote EMT, while at the same time, promote ferroptosis by inhibiting GPX4 ( Bi et al, 2019 ). On the other hand, ferroptosis tendency also contributes to EMT ( Du et al, 2021 ). Erastin, which is an inducer of ferroptosis, can act on lung epithelial cells and causes de-epithelialize ( Sun et al, 2021 ).…”