Pan-cancer analysis of TRPV2 identifies its potential role as a prognostic and immunologic biomarker in oesophageal cancer

Hot beverage drinking has long been confirmed as one of the most notable risk factors for oesophageal cancer [1, 2]. However, the underlying mechanism remains unclear. We read with great interest the publication by Huang et al. [3], which found that transient receptor potential vanilloid receptor 2 (TRPV2), one of the thermally sensitive TRP family members, played an important role in oesophageal cancer tumorigenesis under thermal stress and gave us a molecule-based clue to unravel the association between hot-drinking and oesophageal cancer. Inspired by their work, we conducted a pan-cancer analysis to explore the role of TRPV2 in pan-cancers based on the TCGA database and paid special attention to oesophageal cancer (ESCA).

In our analysis, TRPV2 is abnormally expressed in various cancer types, including ESCA, and the expression of TRPV2 was higher in ESCA compared with adjacent normal tissue (Fig. 1a, P < 0.05). More importantly, when grouped by tumour grade, the expression in the G3 tumour was significantly the highest followed by G2 and then G1 (differentiation: G3 < G2 < G1; invasiveness: G3 > G2 > G1) (Fig. 1b, P < 0.05). The mutation landscape grouped by TRPV2 expression showed that heterogeneity of gene mutation existed in these two groups (Fig. 1c). These results further confirmed that TRPV2 played a role in tumorigenesis of ESCA. Then, the survival analysis showed that TRPV2 expression had prognostic significance in a variety of cancers (Fig. 1d, e), especially ESCA. Grouped by high and low expression of TRPV2, Kaplan–Meier curves were separated for disease-specific survival (DSS) (HR = 1.87, P = 0.03, Fig. 1f) and disease-free survival (DFS) (HR = 2.94, P = 0.02, Fig. 1g) and high TRPV2 expression correlated with poor survival. Further, we employed the CIBERSORT method [4], a robust enumeration method of cell subsets from tissue expression profiles, to explore the relationship between TRPV2 and a wide range of immune cell types. In ESCA, four immune cell types, T_cells_follicular_helper, NK_cells_activated, Eosinophils, and Dendritic_cells_activated were negatively correlated with TRPV2 expression, and T_cells_CD4_memory_resting was positively correlated with TRPV2 expression (Fig. 1h). Finally, we explored the correlation between TRPV2 and immune regulatory genes (Fig. 1i) and immune checkpoints (Fig. 1j) and found that TRPV2 expression strongly correlated with most of them, which might indicate that TRPV2 functions in cancer immunity.

Fig. 1. The role of TRPV2 in pan-cancer analysis.

a The expression of TRPV2 in tumour tissues and the corresponding normal tissues (Wilcoxon rank-sum test). *P < 0.05; **P < 0.01; ***P < 0.001. b The expression of TRPV2 in different tumour grades of ESCA (ANOVA test, G1: well differentiated; G2: moderately differentiated; G3: poorly differentiated). c The waterfall plot of mutation landscape in high and low TRPV2 expression groups in ESCA. d Univariable Cox regression analysis of TRPV2 for DSS (Wald test). e Univariable Cox regression analysis of TRPV2 for DFS (Wald test). f The Kaplan–Meier analysis for DSS in ESCA (grouped by median TRPV2 expression, log-rank test). g The Kaplan–Meier analysis for DFS in ESCA (grouped by median TRPV2 expression, log-rank test). h The correlation analysis between TRPV2 expression and various immune cell types; *P < 0.05 (Pearson correlation analysis). i The correlation analysis between TRPV2 expression and various immune regulatory genes. *P < 0.05 (Pearson correlation analysis). j The correlation analysis between TRPV2 expression and immune checkpoints; *P < 0.05 (Pearson correlation analysis). TRPV2 transient receptor potential vanilloid receptor 2, DSS disease-specific survival, DFS disease-free survival, ACC adrenocortical carcinoma, BLCA bladder urothelial carcinoma, BRCA breast invasive carcinoma, CESC cervical squamous cell carcinoma and endocervical adenocarcinoma, CHOL cholangiocarcinoma, COAD colon adenocarcinoma, DLBC lymphoid neoplasm diffuse large B-cell lymphoma, ESCA oesophageal carcinoma, GBM glioblastoma multiforme, HNSC head and neck squamous cell carcinoma, KICH kidney chromophobe, KIRC kidney renal clear cell carcinoma, KIRP kidney renal papillary cell carcinoma, LAML acute myeloid leukaemia, LGG brain lower-grade glioma, LIHC liver hepatocellular carcinoma, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, MESO mesothelioma, OV ovarian serous cystadenocarcinoma, PAAD pancreatic adenocarcinoma, PCPG pheochromocytoma and paraganglioma, PRAD prostate adenocarcinoma, READ rectum adenocarcinoma, SARC sarcoma, SKCM skin cutaneous melanoma, STAD stomach adenocarcinoma, TGCT testicular germ cell tumours, THCA thyroid carcinoma, THYM thymoma, UCEC uterine corpus endometrial carcinoma, UCS uterine carcinosarcoma, UVM uveal melanoma.

TRPV2 is a calcium-permeable cation channel from the TRPV channel family identified by Caterina et al. in 1999, which can be activated by heat stimuli (>52 °C) [5]. Its expression is high in multiple systems, especially abundant in the brain regions regulating osmoregulation and autonomic regulation, including appetite and circulation systems [5]. TRPV2 acts an important role in signalling pathways mediating cellular processes and exhibits oncogenicity in cancers [6]. Nevertheless, the specific molecular mechanism of TRPV2 in the tumorigenesis of ESCA was not investigated until the work of Huang et al. They discovered that TRPV2 expression was upregulated in cancer cells compared with non-tumour oesophageal squamous cells, and tumour cell proliferation, migration, and tumour-related angiogenesis were promoted when adding 54 °C stimuli or TRPV2 agonist [3]. Their study also indicated the correlation between the high expression level of TRPV2 and poor survival by conducting a Kaplan–Meier analysis. Consistent with their study, our analysis demonstrated that expression of TRPV2 was higher in ESCA tumour tissues compared with normal tissues, and TRPV2 expression was significantly associated with tumour grades. Meanwhile, TRPV2 expression showed a correlation with worse survival status in DSS and DFS for ESCA, which was in accordance with the results of Huang et al. In addition, our study found a relationship between the expression of TRPV2 and tumour immunity, including immune cell infiltration and immune checkpoints. Previous studies have found the specific expression of TRPV2 in multiple immune cells, where it acted as a specialised calcium channel to participate in cell cycle progression, growth, and differentiation in immune-related diseases, including tumours [7]. Moreover, Link et al. discovered the crucial role of TRPV2 in the early process of phagocytosis of macrophages by using TRPV2 knockout mice [8]. TRPV2 was also found to play a crucial role in T lymphocyte connection with antigen-presenting cells as a calcium ion channel, where it forms a cluster at the immunological synapse to trigger T-cell functions [5, 9]. Although the specific mechanisms of how TRPV2 influences tumour immunity are still to be discovered, our results demonstrated the importance of TRPV2 in immune infiltration and should be regarded as a potential biomarker in immunotherapy.

In summary, our analysis further identified the potentially oncogenic role of TRPV2 in ESCA, and TRPV2 might function in cancer immunity by influencing immune infiltration, immune regulatory genes, and immune checkpoints. In the era of multidisciplinary treatment of ESCA, future research could be focused more on the role of TRPV2 in oesophageal cancer immunology and immunotherapy.

Author contributions

HY and YL were involved in conceptualising, literature review and drafting the letter, and YM revised the letter for final submission. All authors approved the final version for submission and publication of the content.

Funding

This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-C&T-B-018).

Data availability

Data used in this study are publicly available from the TCGA database (https://portal.gdc.cancer.gov/).

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.