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Glutathione peroxidase 2 knockdown suppresses gastric cancer progression and metastasis via regulation of kynurenine metabolism.

ABSTRACT: Gastric cancer (GC) is among the most lethal malignancies due to its poor early diagnosis and high metastasis rate, and new therapeutic targets are urgently needed to develop effective anti-GC drugs. Glutathione peroxidase-2 (GPx2) plays various roles in tumor progression and patient survival. Herein, we found that GPx2 was overexpressed and negatively correlated with poor prognosis by using clinical GC samples for validation. GPx2 knockdown suppressed GC proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) in vitro and in vivo. In addition, proteomic analysis revealed that GPx2 expression regulated kynureninase (KYNU)-mediated metabolism. As one of the key proteins involved in tryptophan catabolism, KYNU can degrade the tryptophan metabolite kynurenine (kyn), which is an endogenous ligand for AhR. Next, we revealed that the activation of the reactive oxygen species (ROS)-mediated KYNU-kyn-AhR signaling pathway caused by GPx2 knockdown was involved in GC progression and metastasis. In conclusion, our results showed that GPx2 acted as an oncogene in GC and that GPx2 knockdown suppressed GC progression and metastasis by suppressing the KYNU-kyn-AhR signaling pathway, which was caused by the accumulation of ROS.

SUBMITTER: Xu H

PROVIDER: S-EPMC10256612 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Glutathione peroxidase 2 knockdown suppresses gastric cancer progression and metastasis via regulation of kynurenine metabolism.

Xu Handong H Hu Can C Wang Yi Y Shi Yunfu Y Yuan Li L Xu Jingli J Zhang Yanqiang Y Chen Jiahui J Wei Qin Q Qin Jiangjiang J Xu Zhiyuan Z Cheng Xiangdong X

Oncogene 20230503 24

Gastric cancer (GC) is among the most lethal malignancies due to its poor early diagnosis and high metastasis rate, and new therapeutic targets are urgently needed to develop effective anti-GC drugs. Glutathione peroxidase-2 (GPx2) plays various roles in tumor progression and patient survival. Herein, we found that GPx2 was overexpressed and negatively correlated with poor prognosis by using clinical GC samples for validation. GPx2 knockdown suppressed GC proliferation, invasion, migration and e ...[more]

PMID: 37138031

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Project description:BackgroundRetinoic acid induced 14 (RAI14), also known as NORPEG, is reported as being deregulated in non-small-cell lung cancer, together with having involvement in its cell proliferation as a super enhancer related gene.PurposeThe objective of this study was to investigate the role of RAI14 in the progression and metastasis of gastric cancer and explore the associated mechanism.Materials and methodsGEPIA database was used to analyze the expression of RAI14 in gastric cancer. MNK45 and AGS cells were transfected with siRNA-RAI14 to block the expression of RAI14. Cell Counting Kit 8 and colony formation assays were performed to measure cell proliferation. Cell migration and invasion capacities was examined by transwell assay. Apoptosis rate was detected using flow cytometry, and the protein levels of apoptosis-related proteins was determined using Western blot assay. Reverse-transcription PCR assay was used to detect the expressions of RAB31.ResultsGene expression profiling interactive analysis revealed that RAI14 was substantially upregu-lated in gastric cancer and higher expression of RAI14 was associated with worse prognosis. We also observed that the knockdown of RAI14 by siRNA-RAI14 transfection suppressed growth capacity of MKN45 and AGS cells. Also, RAI14 knockdown inhibited migration and invasion of MKN45 and AGS cells in vitro. Moreover, RAI14 knockdown was observed to accelerate cell apoptosis via down-regulation of Bcl-2 and upregulation of Bax in MKN45 and AGS cells. Furthermore, downregulation of RAI14 inhibited the activation of Akt pathway, and activation of Akt by IGF-1 could restore the reduced proliferation induced by RAI14 knockdown. In addition, we found that RAI14 had a positive correlation with the RAB31 in gastric cancer by GEPIA reverse-transcription PCR and Western blot assays, and the reduced proliferation caused by RAI14 knockdown was restored by RAB31.ConclusionRAI14 knockdown inhibited proliferation, migration and invasion and promoted apoptosis by downregulating the Akt pathway in gastric cancer cells, and RAB31 might be a downstream target gene of RAI14, providing a novel sight into the molecular mechanism of RAI14 and a potential target for gastric cancer treatment.

Dataset Information

Glutathione peroxidase 2 knockdown suppresses gastric cancer progression and metastasis via regulation of kynurenine metabolism.

Publications

Glutathione peroxidase 2 knockdown suppresses gastric cancer progression and metastasis via regulation of kynurenine metabolism.

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