Upregulation of ADAR Promotes Breast Cancer Progression and Serves as a Potential Therapeutic Target

Abstract

Background. Breast cancer (BC) is the most common cause of cancer death worldwide, and its incidence is increasing every year. This study aims to investigate the expression characteristics of ADAR gene in breast cancer and to explore its role in the occurrence and development of BC and its possible mechanism. Methods. TCGA portal was used to detect the expression of ADAR in cancer including BC, and its correlation with clinicopathological data as well as other genes was analyzed via UALCAN database. The TISCH database evaluated the expression of ADAR in different types of cell populations in BC at the single-cell level. The Kaplan–Meier plotter database was used to predict the correlation between ADAR expression and BC patient prognosis. The Human Protein Atlas was used to detect the expression of ADAR in tissues and location of ADAR mRNA in cells. Moreover, the relationships between immune response and ADAR expression in BC were assessed with the use of the TISIDB. Metascape and STRING were applied to predict ADAR with other protein interactions. Finally, the effect generated by ADAR expression on cell proliferating, invading, and migrating processes was assessed in vitro with knockdown and overexpression strategies. Results. ADAR was significantly upregulated in BC tissues compared to paracancerous tissues. Single-cell RNA analysis showed that ADAR was specifically upregulated in cancer cell clusters and was also expressed in stromal and immune cell clusters. The upregulation of ADAR was positively correlated with clinicopathological stage and negatively correlated with BC prognosis. Experimental processes in vitro revealed ADAR knockdown hindered, proliferated, invaded, and migrated levels of BC cells, whereas over expression of ADAR played the opposite effect. ADAR protein, which may interact with OASL, STAT2, and IFIT3, was mainly located in the nucleoli in cells and primarily involved DNA modification and apoptotic signaling pathway. Immune factors may interact with ADAR in BC, and ADAR was found noticeably linked with immunosuppressor such as IL10, CD274, and IDO1. Conclusion. ADAR is significantly upregulated in breast cancer tissues, which may promote the progression of BC through the interaction of cancer cells, stromal cells, and immune cells. Targeting ADAR may offer new hope in treating breast cancer.

ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid

“…By comparison, analysis of the role of the unique genes in MCF7-ERβ1 cells revealed that the regulation of all but one of the hub genes (PPARG, HIPK2, ZFP36L1, HMGB2 and ALDH1A3) and of 12 more unique genes (ASCL1, ID3, GPNMB, SGK3, BAG3, WDR73, ALKBH1, HIGD1A, FGD3, ACAA2, DOCK8 and AGR3) reportedly favors inhibition of breast cancer cell proliferation and tumorigenicity, induction of cell death and/or better clinical outcome [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. In contrast, in ERβ2-expressing cells, the regulation of the two unique hub genes (CXCL12 and SIX4) and of nine of the other unique genes (INHBE, GADD45B, RPS7, IFIT3, IGFBP3, JAG2, BCL3, GPR37L1 and KRT80) reportedly favors inhibition of cell death, resistance of BC to endocrine therapy and poor clinical prognosis [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. Indicative functions reported for all cell-death-related genes uniquely regulated in MCF7-WT, MCF7-ERβ1 and MCF7-ERβ2 cells are presented in Supplementary Tables S10–S12 .…”

OASL knockdown inhibits the progression of stomach adenocarcinoma by regulating the mTORC1 signaling pathway

“…17 OASL may interact with ADAR to promote the proliferation and migration of breast cancer cells. 30 However, the effect of OASL on the progression of STAD has not been reported. In our study, cell experiments verified that OASL knockdown inhibited cell proliferation, migration, and invasion, but promoted apoptosis in STAD cells.…”

“…High OASL expression is associated with poor prognosis in patients with PDAC 17 . OASL may interact with ADAR to promote the proliferation and migration of breast cancer cells 30 . However, the effect of OASL on the progression of STAD has not been reported.…”

Suppression of AGRN enhances CD8+ T cell recruitment and inhibits breast cancer progression

“…We downloaded the data for protein‐protein interaction (PPI) network construction from the STRING online database. Details were shown in previous research 30 …”