AKR1C2 acts as a targetable oncogene in esophageal squamous cell carcinoma via activating PI3K/AKT signaling pathway

Abstract

The aldo‐keto reductases family 1 member C2 (AKR1C2) has critical roles in the tumorigenesis and progression of malignant tumours. However, it was also discovered to have ambiguous functions in multiple cancers and till present, its clinical significance and molecular mechanism in oesophageal squamous cell carcinoma (ESCC) has been unclear. The aim of this study was to explore the role of AKR1C2 in the tumorigenesis of ESCC. Here, we showed that AKR1C2 expression was found to be up‐regulated in ESCC tissues and was significantly associated with pathological stage, lymph node metastasis and worse outcomes. Functional assays demonstrated that an ectopic expression of AKR1C2 in ESCC cells resulted in increased proliferation, migration and cisplatin resistance, while knockdown led to inversing effects. Bioinformation analyses and mechanistic studies demonstrated that AKR1C2 activated the PI3K/AKT signalling pathway, furthermore, the inhibitor of PI3K or the selective inhibitor of AKR1C2 enzyme activity could reverse the aggressiveness and showed synergistic antitumour effect when combined with cisplatin, both in vitro and in vivo. In conclusion, Our findings revealed that AKR1C2 could function as an oncogene by activating the PI3K/AKT pathway, as a novel prognostic biomarker and/or as a potential therapeutic target to ESCC.

A novel immune-related gene signature predicts survival in esophageal squamous cell carcinoma

“…Ultimately, the PPI network was constructed by 23 hub genes that were significantly related to this pathway ( Figure 6I ). We found that numerous genes, such as ADH7 ( 12 ), AKR1C2 ( 13 ), ALDH2 ( 14 ), NQO1 ( 15 ), ADH1C ( 12 ), EPHX1 ( 16 ), BLVRB ( 17 ), HMOX1 ( 18 ), ABCC3 ( 19 ), ALDH3A1 ( 20 ), and IDH1 ( 21 , 22 ), are related to ESCC tumor susceptibility, tumorigenesis, and progression.…”

“…Also, Ren et al noted that ESCC tumors frequently expressed heme oxygenase 1 (HO-1), and knockdown of HO-1 promoted apoptosis through activation of a reactive oxygen species (ROS)-mediated caspase apoptosis pathway ( 18 ). Zhang et al revealed that AKR1C2 could function as an oncogene (via activation of the PI3K/AKT pathway) and a novel prognostic biomarker and/or a potential therapeutic target in ESCC ( 13 ). In contrast, the mitotic spindle, glycolysis, PI3K/AKT/MTOR signaling, G2M checkpoint, and unfolded protein response pathways were significantly up-regulated in the low risk score group of the immunity_H cluster ( Figure 6B,C,D,E,F ).…”

Comprehensive analysis regarding the prognostic significance of downregulated ferroptosis-related gene AKR1C2 in gastric cancer and its underlying roles in immune response

“…A study indicated that AKR1C2 expression is correlated with fat distribution of human bodies [ 32 ], and AKR1C2 plays a vital role in the process of some cancers. A study also identified that AKR1C2 could be an oncogene in esophageal squamous cell carcinoma through mediating PI3K/AKT pathway [ 33 ]. The down-regulated expression level of AKR1C2 combined with upregulated expression of SRD5A1 and SRD5A3 may lead to the high levels of DHT either in primary or metastatic prostate cancer [ 34 ].…”