Most of the multifunctional family of ion channels formed by TRP channels were calcium-permeable, shown intricate patterns of regulation and were sensitive to a wide range of environmental conditions. Some studies indicated that ion channels may hold a key role in the induction and progression of carcinoma. Several studies in breast cancer revealed that potassium (K+) channels[30, 31] were engaged in the processes of cell proliferation, cell cycle progression, as well as metastasis. Fraser et al. found that the activities of sodium (Na+) channels were associated with the progression and invasion of breast carcinoma. Since 1969, TRP channels were firstly discovered in drosophila by Cosens and Manning, the role of TRP channels in malignant tumors continues to be identified. The roles of different TRP subfamily members were varied in different kinds of neoplasm. Gkika and colleagues conducted a study of TRP channels in prostate cancer, suggesting that TRPM8 and TRPV6 were novel markers for tumor progression. In hepatocellular carcinoma, TRPV2 was identified as a potential prognostic factor due to the correlation of tumor differentiation and TPRV2 gene expression. He B et al. found that the invasion abilities of nasopharyngeal cancer cells could be inhibited by silencing the expression of TRPC1 in tumor cells. Besides, the pharmacological inhibitors for TPRC1 could make the cell cycle of malignant glioma stagnating to suppress the tumor cell proliferation. In esophageal carcinoma, TRPC6 was proposed as a potential target for treatment by Ding and colleagues, which was associated with the growth of tumor cells.
Breast cancer is a kind of highly heterogeneous tumor with a high rate of proliferation, invasion, and metastasis, which was associated with the microenvironment changes. The development of mammary tumor was considered associated with the deregulation of Ca2+ homeostasis[38, 39]. In 2003, the calcium channels were firstly discovered to play a regulator role in breast tumor malignant transformation. After that, the correlation between Ca2+ homeostasis and breast tumor progression were further explored. Some TRP subfamily members were suggested to play vital roles in growth and migration of BC cells, including TRPM7, TRPC1, and TPRV6. In addition, a number of academics investigated in the relationship among TRP channels and clinical characteristics in BC. Recently, several TRPs were reported highly overexpressed in invasive ductal carcinoma (IDC), for example TRPC6, TRPM7, TRPM8, TRPV6 and TRPC1[43, 44]. As such, TRPs were proposed by some scholars to be play as novel biomarkers for BC diagnosis and treatment. Despite of multiple approaches were developed for antitumor, patients suffered from advanced BC were still considered a big medical challenge. Recently, more and more academics focused on the potential ability of TRP channel to be as the targets of anticancer therapy. However, knowledge about the relationship between TPR channels and immunotherapy is lacking. Hence, we explored the correlation of TRP-related lncRNAs and the prognostic outcomes of BC patients to identify the potential targets for BC immunotherapy.
In our study, the prognostic lncRNAs associated with TRP channels were identified by the analysis of lncRNA expression in BC samples from TCGA data. After that, the 12-TRP-related-lncRNA risk model was established to divide the BC patients in training set and validation set into high-risk groups and low-risk groups according to the median cut-off value of training set. Interestingly, a significant distinction in prognostic outcomes was observed between different risk groups via survival analysis. The AUCs of the 12-lncRNA-based risk scores in training ser for the 5-, 7- and 10-year OS predictors were 0.752, 0.822 and 0.833, respectively. Subsequently, we created a lncRNA-mRNA co-expression network and conducted functional enrichment analysis. Notably, biological processes associated with immunology was identified highly enriched, including but not limited to immune cell activation and immune response. Therefore, the infiltration of immune cells was further investigated to identify the features of TRP-related tumor immune microenvironment.
Recently, some academics focused on the role of TRP channels in calcium signaling and immunomodulation. Calcium is core to a number of biological processes, for example, the activation and maintenance of the immune system. As of now, store-operated calcium entry (SOCE) was the most widely known mechanism of calcium ion infusion into cells, that was the key to immune cell activation. TRP channels were engaged in a variety of biological processes in the immune system, involving activation of B and T cell receptor, antigen presentation via DCs, degranulation of mast cell as well as bactericidal activities of macrophage and neutrophil. Some studies indicated that TRP channels were significant for the initiation of adaptive and innate immune response. Several studies proved that the TRP channels were expressed both in the murine T cells[46, 47] and human T cells, such as TRPV, TRPC, TRPA and TRPM. TRPC5 was identified as an immunosuppressor associated with CD4+ and CD8+ T cell activation. TPRC3 was reported to be upregulated in response to the stimulation of multiclonal T cells, further promoting the proliferation of cells associated with Ca2+. Moreover, some studies indicated that TRPV1 and TRPV2 were expressed not only in human leukocytes/lymphocytes but also in CD4+ T cells[50, 51]. Besides, several TRP channels were suggested to be expressed in primary human B cells, including TRPC2, TRPC6, TPRV2 and TPRM7[52–54]. TRPC channels were demonstrated to be involved in B cell receptor signaling. Simultaneously, TPRM channels were found to play important roles in cell proliferation and intracellular tracking regulation. As for innate immune system, recent research revealed that TRP channels were involved in the Ca2+ homeostasis in NK cells[28, 55]. TRPV and TRPM channels were identified linked to DCs function, including thermosensation, antigen presentation, trafficking and migration[26, 56]. In addition, there was increasing evidence that TRP channels were essential for monocytes, macrophages, neutrophils, and mast cells. TRPC1 has been demonstrated associated with neutrophil migration in murine. TRPV2 was reported to be a participant in macrophage chemotaxis and cytokine production[58, 59]. The study in asthmatic rats revealed that TRPM7 channel played a key in mast cell function, for instance, degranulation and cytokine release. According to our research, TRP-related lncRNA risk model was associated with the infiltration of immune cells. Hence, we hypothesized that the expression of TRP channels could be closely related to alterations in the tumor immune microenvironment. However, seldom studies investigated the regulating mechanisms of TRP channels in TIME.
Since the outcomes linked the TRP-related lncRNA signature to immune cell infiltration in breast cancer, these TRP-related lncRNAs may be the novel targets for immunotherapies, such as immune checkpoint inhibitors. According to the results of our study, low-risk group based on 12-TRP-lncRNA risk model presented higher immune checkpoint molecules expression levels with better prognosis. Besides, IPS and MSI analysis were further indicated that lower risk scores meant better immunotherapy response. As such, the TRP-associated-lncRNA risk model was considered as a predictor for immunotherapy response in patients with breast cancer, which was able to facilitate the development of novel treatment strategies.
Our study was the first one to construct a TRP-associated-lncRNA risk model based on 12 TRP-related lncRNAs by use of public databases, considered as independent factor for prognosis predicter in patients with breast cancer. However, there are still some limitations in our study. Firstly, a single data collected from TCGA database was enrolled in this study. Secondly, due to the incomplete clinical information, some other prognostic features were excluded out univariate and multivariate COX regression analysis, for example immunotherapy, chemotherapy, and radiotherapy data. Thirdly, this study only explored the relationship between the TRP-associated-lncRNA signature and infiltration of immune cells, while seldom investigated the immune regulating mechanisms of TRP channels. Consequently, additional validation experiments are essential to confirm the prognostic predictive efficiency of this signature and the correlation of TRP channels and tumor immune microenvironment should be further studied. We provided a novel insight for anti-tumor immunity in breast cancer.