UHMK1 promotes lung adenocarcinoma oncogenesis by regulating the PI3K/AKT/mTOR signaling pathway

Abstract

Background Effective targeted therapy for lung adenocarcinoma (LUAD), the number one cancer killer worldwide, continues to be a difficult problem because of the limitation of number of applicable patients and acquired resistance. Identifying more promising drug targets for LUAD treatment holds immense clinical significance. Recent studies have revealed that the U2 auxiliary factor (U2AF) homology motif kinase 1 (UHMK1) is a robust pro‐oncogenic factor in many cancers. However, its biological functions and the underlying molecular mechanisms in LUAD have not been investigated. Methods The UHMK1 expression in LUAD cells and tissues was evaluated by bioinformatics analysis, immunohistochemistry (IHC), western blotting (WB), and real time quantitative polymerase chain reaction (RT‐qPCR) assays. A series of gain‐ and loss‐of‐function experiments for UHMK1 were carried out to investigate its biological functions in LUAD in vitro and in vivo. The mechanisms underlying UHMK1's effects in LUAD were analyzed by transcriptome sequencing and WB assays. Results UHMK1 expression was aberrantly elevated in LUAD tumors and cell lines and positively correlated with tumor size and unfavorable patient prognosis. Functionally, UHMK1 displayed robust pro‐oncogenic capacity in LUAD and mechanistically exerted its biological effects via the phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Conclusion UHMK1 is a potent oncogene in LUAD. Targeting UHMK1 may significantly improve the effect of LUAD treatment via inhibiting multiple biological ways of LUAD progression.

The oncogenic role of LGR6 overexpression induced by aberrant Wnt/β‐catenin signaling in lung cancer

“…Dimethylarginine dimethylaminohydrolase‐1, encoded by DDAH1 , is overexpressed in various human cancers and is involved in tumor angiogenesis 58 . UHMK1 , which encodes the protein U2 auxiliary factor homology motif kinase 1, 59 is overexpressed in lung adenocarcinomas and functions as an oncogene via activation of the PI3K/AKT mTOR pathway 60 . GNB4 is highly expressed in urothelial carcinoma, esophageal squamous cell carcinoma, gastric cancer, and head and neck squamous cell carcinoma, and is a stemness‐related gene 61–64 .…”

“… 58 UHMK1 , which encodes the protein U2 auxiliary factor homology motif kinase 1, 59 is overexpressed in lung adenocarcinomas and functions as an oncogene via activation of the PI3K/AKT mTOR pathway. 60 GNB4 is highly expressed in urothelial carcinoma, esophageal squamous cell carcinoma, gastric cancer, and head and neck squamous cell carcinoma, and is a stemness‐related gene. 61 , 62 , 63 , 64 In terms of common DEGs putatively downregulated by LGR6, CKAP4 encodes a Dickkopf (DKK1)‐binding protein in the plasma membrane and participates in the regulation of Wnt/β‐catenin signaling.…”